Methods and compositions for terpenoid tricycloalkane synthesis

ABSTRACT

In one aspect, the disclosure relates to methods for preparation of intermediates useful for the preparation of terpenoid cores. In a further aspect, the disclosed methods pertain to the preparation of compounds comprising a terpenoid core or scaffold, such as 6/7/5 tricycloalkanes. The disclosed methods utilize abundant starting materials and simple reaction sequences that can be used to tunably and scalably assemble common terpenoid cores. In various aspects, the present disclosure pertains to compounds prepared using the disclosed methods. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present disclosure.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of, and claims priority to,co-pending U.S. application Ser. No. 15/981,833, filed May 16, 2018,which application is incorporated herein fully by this reference.

BACKGROUND

Structurally complex terpenoid natural products have been recognized asimportant therapeutic agents. For example, taxol and ingenol areclinically used for the treatment of cancer and actinic keratosis,respectively. In addition to these important drugs, a multitude ofrelated cycloheptane-containing terpenoid natural products havepromising, but underexplored medicinal potential. For instance, englerinA and its analogs are being actively investigated for the treatment ofrenal cancer, phorbol and its esters have been intensely studied due totheir potent biological activities, as have pseudoguaianolide naturalproducts. Numerous other natural product classes, including abeo-taxane,neodolastane, cyathane, and icetexane, and individual natural products,such as anthecularin, sandresolide B, frondosin A, and liphagal displaypromising biological activities. The combination of the polycycliccarbon -framework's rigidity and differences resulting from thesubstitution and oxidation patterns thereon provide a rich array ofpotential biological activities. Other therapeutically and chemicallyinteresting terpenoids are shown in FIG. 1.

Facile and systematic access to diverse substitution and oxidationpatterns about carbocyclic frameworks would advance drug design anddevelopment. Accordingly, simplifying access to complex terpenoidscaffolds for application in the drug discovery process is a major goalof modern organic chemistry (e.g., see Huang, M., et al., Expert Opin.Investig. Drugs 2012, 21, 1801; Ghantous, A., et al., Drug Discov. Today2010, 15, 668; and Wang, G., et al., In Nat. Prod.; Humana Press Inc.,2005; pp 197-227). For example, natural product analogs can be accessedby (a) semisynthesis (see Ganem, B.; Franke, R. R. J. Org. Chem. 2007,72, 3981), (b) “total” or de novo synthesis (e.g., see Jansen, D. J.;Shenvi, R. A. Future Med. Chem. 2014, 6, 1127; Urabe, D.; Asaba, T.;Inoue, M. Chem. Rev. 2015, 115, 9207; and Maimone, T. J.; Baran, P. S.Nat Chem Biol 2007, 3 (7), 396), and by (c) diversity-oriented synthesis(e.g., see Cordier, C., et al., Nat. Prod. Rep. 2008, 25, 719; HuigensIII, R. W., et al., Nat. Chem. 2013, 5, 195; Balthaser, B. R., et al.,Nat Chem 2011, 3, 969; and McLeod, M. C., et al., Nat. Chem. 2014, 6,133). However, many of these synthetic approaches are laborious andrequire complex reaction sequences, frequently use starting materialsthat are costly and rare; and/or are not easily scalable. Currentlyavailable synthetic routes do not provide methods that allow facilepreparation of diverse terpenoid scaffolds that can be derivatized forbiological evaluation.

Despite advances in research directed towards preparation of terpenoidcores and scaffolds, there remain a scarcity of methods for preparationof terpenoid cores that utilize abundant starting materials and simplereaction sequences that can be used to tunably and scalably assemblecommon terpenoid cores. Moreover, in view of the limitations of currentmethods, there are limited compounds comprising a terpenoid core thatcan be easily derivatized for biological evaluation. These needs andother needs are satisfied by the present disclosure.

SUMMARY

In accordance with the purpose(s) of the disclosure, as embodied andbroadly described herein, the disclosure, in one aspect, relates tomethods for preparation of intermediates useful for the preparation ofterpenoid cores. In a further aspect, the disclosed methods pertain tothe preparation of compounds comprising a terpenoid core or scaffold,such as 6/7/5 tricycloalkanes. The disclosed methods utilize abundantstarting materials and simple reaction sequences that can be used totunably and scalably assemble common terpenoid cores. In variousaspects, the present disclosure pertains to compounds prepared using thedisclosed methods.

Disclosed are compounds having a formula represented by a structure:

wherein E is —CN or —(C═O)OR¹⁰; wherein R¹⁰ is C1-C6 alkyl; wherein eachof R^(1a), R^(1b), R^(1c), and R^(1d) is independently hydrogen, C1-C6alkyl, aryl, or —(CH₂)_(m)(C═O)OR¹¹; or wherein R^(1a) and R^(1c) arecovalently bonded and, together with more intermediate carbons, comprise—CH₂CH₂—, or —CH═CH—; wherein m is an integer selected from 0, 1, 2, and3; and wherein R¹¹ is C1-C6 alkyl; wherein R² is hydrogen, C1-C6 alkyl,aryl, or —(CH₂)_(n)(C═O)OR¹²; wherein n is an integer selected from 0,1, 2, and 3; and wherein R¹² is C1-C6 alkyl; wherein A¹ is—C(R²⁰)(R²¹)—, —NR²²— or —CH₂—; wherein R²⁰ is hydrogen, C1-C6 alkyl, or—(CH₂)_(p)C═O)OR³⁰; wherein R³⁰ is C1-C6 alkyl; and wherein p is aninteger selected from 0, 1, 2, and 3; wherein R²¹ is hydrogen, C1-C6alkyl, or —(CH₂)_(q)C═O)OR³⁰; wherein R³¹ is C1-C6 alkyl; and wherein qis an integer selected from 0, 1, 2, and 3; and wherein R²² is C1-C6alkyl, or —(C═O)OR³²; and wherein R³² is C1-C6 alkyl.

Also disclosed herein are compounds having a formula represented by astructure:

wherein E is —CN or —(C═O)OR¹⁰; wherein R¹⁰ is C1-C6 alkyl; wherein eachof R^(1a), R^(1b), R^(1c), and R^(1d) is independently hydrogen, C1-C6alkyl, aryl, or —(CH₂)_(m)(C═O)OR¹¹; or wherein R^(1a) and R^(1c) arecovalently bonded and, together with more intermediate carbons, comprise—CH₂CH₂—, or —CH═CH—; wherein m is an integer selected from 0, 1, 2, and3; and wherein R¹¹ is C1-C6 alkyl; wherein R² is hydrogen, C1-C6 alkyl,aryl, or —(CH₂)_(n)(C═O)OR¹²; wherein n is an integer selected from 0,1, 2, and 3; and wherein R¹² is C1-C6 alkyl; wherein A¹ is—C(R²⁰)(R²¹)—, —NR²²— or —CH₂—; wherein R²⁰ is hydrogen, C1-C6 alkyl, or—(CH₂)_(p)C═O)OR³⁰; wherein R³⁰ is C1-C6 alkyl; and wherein p is aninteger selected from 0, 1, 2, and 3; wherein R²¹ is hydrogen, C1-C6alkyl, or —(CH₂)_(q)C═O)OR³⁰; wherein R³¹ is C1-C6 alkyl; and wherein qis an integer selected from 0, 1, 2, and 3; and wherein R²² is C1-C6alkyl, or —(C═O)OR³²; and wherein R³² is C1-C6 alkyl; wherein R³ ishydrogen, C1-C6 alkyl, aryl, trimethylsilyl, or —(CH₂)_(r)(C═O)OR¹⁵;wherein r is an integer selected from 0, 1, 2, and 3; and wherein R¹⁵ isC1-C6 alkyl.

Also disclosed herein are methods of synthesizing an allenyne precursorto a terpenoid scaffold, the method comprising: reacting a γ-allenylKnoevenagel adduct and a propargyl electrophile in the presence of ametal hydride; wherein the γ-allenyl Knoevenagel adduct has a formularepresented by a structure:

wherein E is —CN or —(C═O)OR¹⁰; wherein R¹⁰ is C1-C6 alkyl; wherein eachof R^(1a), R^(1b), R^(1c), and R^(1d) is independently hydrogen, C1-C6alkyl, aryl, or —(CH₂)_(m)(C═O)OR¹¹; or wherein R^(1a) and R^(1c) arecovalently bonded and, together with more intermediate carbons, comprise—CH₂CH₂—, or —CH═CH—; wherein m is an integer selected from 0, 1, 2, and3; and wherein R¹¹ is C1-C6 alkyl; wherein R² is hydrogen, C1-C6 alkyl,aryl, or —(CH₂)_(n)(C═O)OR¹²; wherein n is an integer selected from 0,1, 2, and 3; and wherein R¹² is C1-C6 alkyl; wherein A¹ is—C(R²⁰)(R²¹)—, —NR²²— or —CH₂—; wherein R²⁰ is hydrogen, C1-C6 alkyl, or—(CH₂)_(p)C═O)OR³⁰; wherein R³⁰ is C1-C6 alkyl; and wherein p is aninteger selected from 0, 1, 2, and 3; wherein R²¹ is hydrogen, C1-C6alkyl, or —(CH₂)_(q)C═O)OR³⁰; wherein R³¹ is C1-C6 alkyl; and wherein qis an integer selected from 0, 1, 2, and 3; and wherein R²² is C1-C6alkyl, or —(C═O)OR³²; and wherein R³² is C1-C6 alkyl; and, wherein thepropargyl electrophile has a formula represented by a structure:

wherein R³ is hydrogen, C1-C6 alkyl, aryl, trimethylsilyl, or—(CH₂)_(r)(C═O)OR¹⁵; wherein r is an integer selected from 0, 1, 2, and3; and wherein R¹⁵ is C1-C6 alkyl; thereby synthesizing the allenyneprecursor to the terpenoid scaffold; wherein the allenyne precursor tothe terpenoid scaffold has a formula represented by a structure:

While aspects of the present disclosure can be described and claimed ina particular statutory class, such as the system statutory class, thisis for convenience only and one of skill in the art will understand thateach aspect of the present disclosure can be described and claimed inany statutory class. Unless otherwise expressly stated, it is in no wayintended that any method or aspect set forth herein be construed asrequiring that its steps be performed in a specific order. Accordingly,where a method claim does not specifically state in the claims ordescriptions that the steps are to be limited to a specific order, it isno way intended that an order be inferred, in any respect. This holdsfor any possible non-express basis for interpretation, including mattersof logic with respect to arrangement of steps or operational flow, plainmeaning derived from grammatical organization or punctuation, or thenumber or type of aspects described in the specification.

BRIEF DESCRIPTION OF THE FIGURES

The accompanying figures, which are incorporated in and constitute apart of this specification, illustrate several aspects and together withthe description serve to explain the principles of the disclosure.

FIG. 1 shows representative 6/7/5 tricycloalkane terpenes.

FIG. 2 shows a representative disclosed synthesis for the preparation of6/7/5 tricycloalkane terpenoid cores or scaffolds.

FIGS. 3A-3B show representative disclosed syntheses for the preparationof 1,7-allenynes. FIG. 3A shows a generalized reaction scheme used toprepare 1,7-allenyne having structure 5 as shown in the figure. FIG. 3Bshows specific representative 1,7 allenynes prepared, with the reactionsequences used and percent yield indicated by the compound labelsbeneath the product structure. The compound labels shown in FIGS. 3A-3B,i.e., 2 a-2 e, 3 a-3 f, 4 a-4 f, etc., refer to the compound labels usedin the Examples herein below. In the reactions shown in FIGS. 3A-3B, thestandard protocol was as follows: about 300 mg to about 2 g of 1,5-eynesubstrate 3 a-3 f, toluene (0.1 M), 150° C., then swap toluene for THF(0.5 M), add NaH (1.1 equivalent), and propargyl bromide derivative (1.5equivalents). In the figures and herein throughout, “rt” indicates roomtemperature.

FIGS. 4A-4C show representative reaction sequences for 1,5-enynes thateither do or do not undergo [3,3] rearrangement. FIG. 4A shows anexemplary 1,5-enyne that does not undergo [3,3] rearrangement. FIG. 4Bshows a specific representative reaction sequence for 1,5-enynes that doundergo [3,3] rearrangement. FIG. 4C shows specific representativecompounds that are prepared from 1,5-enynes that undergo [3,3]rearrangement. The compound labels shown in FIGS. 4A-4C, i.e., 3 h-3 k,2 d, 5 hd-5 kd, etc., refer to the compound labels used in the Examplesherein below. In the reactions shown in FIGS. 4A-4C, the standardprotocol was as follows: about 300 mg of 1,5-eyne substrate 3 h-3 k,toluene (0.1 M), 150 ° C., then swap toluene for THF (0.5 M), add NaH(1.1 equivalent), and propargyl bromide derivative 2 d (1.5equivalents).

FIGS. 5A-5C show representative disclosed syntheses for the preparationof various allene/tethered π-systems prepared using the disclosedmethods. FIG. 5A shows a generalized reaction scheme used to prepareallene/tethered π-systems having structures 7 a, 7 b, and 7 c as shownin the figure with the substitutions and product yields as indicated inthe figure. FIG. 5B show a specific representative reaction sequenceused to prepare a representative allene/tethered π-system compound. FIG.5C shows a specific representative reaction sequence used to prepare arepresentative allene/tethered π-system compound. The compound labelsshown in FIGS. 5A-5C, i.e., 3 e, 7 a, 7 b, 7 c, 7 d, 7 e, and 7 f, referto the compound lables used in the Examples herein below. In thereactions shown in FIGS. 5A-5C, the standard protocol was as follows:about 300 mg of 1,5-eyne substrate 3 e, toluene (0.1 M), 150° C., thenswap toluene for THF (0.5 M), add NaH (1.1 equivalent), and alkyl halidederivative 2 d (1.5 equivalents).

FIGS. 6A-6B show representative disclosed syntheses for the preparationof of 6/7/5 tricycloalkane frameworks. FIG. 6A show a specificrepresentative reaction sequence used to prepare a representative 6/7/5tricycloalkane framework. FIG. 6B shows specific representative 6/7/5tricycloalkane prepared, with the reaction sequences used and percentyield indicated by the compound labels beneath the product structure.The compound labels shown in FIGS. 6A-6B, i.e., 5 aa, 6 aa, 5 cd, etc.refer to the compound lables used in the Examples herein below. In thereactions shown in FIGS. 6A-6B, the standard protocol was as follows:about 500 mg of allenyne 5, 1 atm CO, 10 mol% [Rh(CO)₂Cl]₂, p-xylene(0.005 M), 110° C.

FIGS. 7A-7B show representative disclosed syntheses for the preparationof representative disclosed compounds. FIG. 7A shows a representativedisclosed compound prepared by a representative intramolecularDiels-Alder furan reaction. FIG. 7B shows 6/6/7 tricycloalkane naturalproducts related in structure to the representative disclosed compoundshown in FIG. 7A. The compound labels shown in FIGS. 7A-7B, i.e., 7 eand 8 refer to the compound lables used in the Examples herein below.

FIGS. 8A-8B show representative disclosed syntheses for therepresentative disclosed functional group interconversion reactions.FIG. 8A shows the preparation of compounds 9 a and 9 b from compound 6dd, with the specific functional group interconversion dependent uponthe reaction conditions used as shown in the figure. FIG. 8B shows thepreparation of compounds 9 c and 9 d from compound 6 kd, with thespecific functional group interconversion dependent upon the reactionconditions used as shown in the figure (see footnotes). The compoundlabels shown in FIGS. 8A-8B, i.e., 6 dd, 9 a, 9 b, 6 kd, 9 c, and 9 drefer to the compound lables used in the Examples herein below.

Additional advantages of the disclosure will be set forth in part in thedescription which follows, and in part will be obvious from thedescription, or can be learned by practice of the disclosure. Theadvantages of the disclosure will be realized and attained by means ofthe elements and combinations particularly pointed out in the appendedclaims. It is to be understood that both the foregoing generaldescription and the following detailed description are exemplary andexplanatory only and are not restrictive of the disclosure, as claimed.

DETAILED DESCRIPTION

The present disclosure can be understood more readily by reference tothe following detailed description of the disclosure and the Examplesincluded therein.

A. Definitions

As used in the specification and the appended claims, the singular forms“a,” “an” and “the” include plural referents unless the context clearlydictates otherwise. Thus, for example, reference to “a functionalgroup,” “an alkyl,” or “a residue” includes mixtures of two or more suchfunctional groups, alkyls, or residues, and the like.

Ranges can be expressed herein as from “about” one particular value,and/or to “about” another particular value. When such a range isexpressed, a further aspect includes from the one particular valueand/or to the other particular value. Similarly, when values areexpressed as approximations, by use of the antecedent “about,” it willbe understood that the particular value forms a further aspect. It willbe further understood that the endpoints of each of the ranges aresignificant both in relation to the other endpoint, and independently ofthe other endpoint. It is also understood that there are a number ofvalues disclosed herein, and that each value is also herein disclosed as“about” that particular value in addition to the value itself. Forexample, if the value “10” is disclosed, then “about 10” is alsodisclosed. It is also understood that each unit between two particularunits are also disclosed. For example, if 10 and 15 are disclosed, then11, 12, 13, and 14 are also disclosed.

References in the specification and concluding claims to parts by weightof a particular element or component in a composition denotes the weightrelationship between the element or component and any other elements orcomponents in the composition or article for which a part by weight isexpressed. Thus, in a compound containing 2 parts by weight of componentX and 5 parts by weight component Y, X and Y are present at a weightratio of 2:5, and are present in such ratio regardless of whetheradditional components are contained in the compound.

A weight percent (wt. %) of a component, unless specifically stated tothe contrary, is based on the total weight of the formulation orcomposition in which the component is included.

As used herein, nomenclature for compounds, including organic compounds,can be given using common names, IUPAC, IUBMB, or CAS recommendationsfor nomenclature. When one or more stereochemical features are present,Cahn-lngold-Prelog rules for stereochemistry can be employed todesignate stereochemical priority, E/Z specification, and the like. Oneof skill in the art can readily ascertain the structure of a compound ifgiven a name, either by systemic reduction of the compound structureusing naming conventions, or by commercially available software, such asCHEMDRAW™ (Cambridgesoft Corporation, U.S.A.).

As used herein, the term “substituted” is contemplated to include allpermissible substituents of organic compounds. In a broad aspect, thepermissible substituents include acyclic and cyclic, branched andunbranched, carbocyclic and heterocyclic, and aromatic and nonaromaticsubstituents of organic compounds. Illustrative substituents include,for example, those described below. The permissible substituents can beone or more and the same or different for appropriate organic compounds.For purposes of this disclosure, the heteroatoms, such as nitrogen, canhave hydrogen substituents and/or any permissible substituents oforganic compounds described herein which satisfy the valences of theheteroatoms. This disclosure is not intended to be limited in any mannerby the permissible substituents of organic compounds. Also, the terms“substitution” or “substituted with” include the implicit proviso thatsuch substitution is in accordance with permitted valence of thesubstituted atom and the substituent, and that the substitution resultsin a stable compound, e.g., a compound that does not spontaneouslyundergo transformation such as by rearrangement, cyclization,elimination, etc. It is also contemplated that, in certain aspects,unless expressly indicated to the contrary, individual substituents canbe further optionally substituted (i.e., further substituted orunsubstituted).

In defining various terms, “A¹,” “A²,” “A³,” and “A⁴” are used herein asgeneric symbols to represent various specific substituents. Thesesymbols can be any substituent, not limited to those disclosed herein,and when they are defined to be certain substituents in one instance,they can, in another instance, be defined as some other substituents.

The term “aliphatic” or “aliphatic group,” as used herein, denotes ahydrocarbon moiety that may be straight-chain (i.e., unbranched),branched, or cyclic (including fused, bridging, and spirofusedpolycyclic) and may be completely saturated or may contain one or moreunits of unsaturation, but which is not aromatic. Unless otherwisespecified, aliphatic groups contain 1-20 carbon atoms. Aliphatic groupsinclude, but are not limited to, linear or branched, alkyl, alkenyl, andalkynyl groups, and hybrids thereof such as (cycloalkyl)alkyl,(cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

The term “alkyl” as used herein is a branched or unbranched saturatedhydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, s -butyl, t-butyl, n-pentyl,isopentyl, s-pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl,dodecyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, and the like. Thealkyl group can be cyclic or acyclic. The alkyl group can be branched orunbranched. The alkyl group can also be substituted or unsubstituted.For example, the alkyl group can be substituted with one or more groupsincluding, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether,halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol, as described herein.A “lower alkyl” group is an alkyl group containing from one to six(e.g., from one to four) carbon atoms. The term alkyl group can also bea C1 alkyl, C1-C2 alkyl, C1-C3 alkyl, C1-C4 alkyl, C1-C5 alkyl, C1-C6alkyl, C1-C7 alkyl, C1-C8 alkyl, C1-C9 alkyl, C1-C10 alkyl, and the likeup to and including a C1-C24 alkyl.

Throughout the specification “alkyl” is generally used to refer to bothunsubstituted alkyl groups and substituted alkyl groups; however,substituted alkyl groups are also specifically referred to herein byidentifying the specific substituent(s) on the alkyl group. For example,the term “halogenated alkyl” or “haloalkyl” specifically refers to analkyl group that is substituted with one or more halide, e.g., fluorine,chlorine, bromine, or iodine. Alternatively, the term “monohaloalkyl”specifically refers to an alkyl group that is substituted with a singlehalide, e.g. fluorine, chlorine, bromine, or iodine. The term“polyhaloalkyl” specifically refers to an alkyl group that isindependently substituted with two or more halides, i.e. each halidesubstituent need not be the same halide as another halide substituent,nor do the multiple instances of a halide substituent need to be on thesame carbon. The term “alkoxyalkyl” specifically refers to an alkylgroup that is substituted with one or more alkoxy groups, as describedbelow. The term “aminoalkyl” specifically refers to an alkyl group thatis substituted with one or more amino groups. The term “hydroxyalkyl”specifically refers to an alkyl group that is substituted with one ormore hydroxy groups. When “alkyl” is used in one instance and a specificterm such as “hydroxyalkyl” is used in another, it is not meant to implythat the term “alkyl” does not also refer to specific terms such as“hydroxyalkyl” and the like.

The term “alkenyl” as used herein is a hydrocarbon group of from 2 to 24carbon atoms with a structural formula containing at least onecarbon-carbon double bond. Asymmetric structures such as (A¹A²)C═C(A³A⁴)are intended to include both the E and Z isomers. This can be presumedin structural formulae herein wherein an asymmetric alkene is present,or it can be explicitly indicated by the bond symbol C═C. The alkenylgroup can be substituted with one or more groups including, but notlimited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl,cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester,ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, orthiol, as described herein.

The term “alkynyl” as used herein is a hydrocarbon group of 2 to 24carbon atoms with a structural formula containing at least onecarbon-carbon triple bond. The alkynyl group can be unsubstituted orsubstituted with one or more groups including, but not limited to,alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl,aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether,halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, asdescribed herein.

The term “aromatic group” as used herein refers to a ring structurehaving cyclic clouds of delocalized π electrons above and below theplane of the molecule, where the π clouds contain (4n+2) π electrons. Afurther discussion of aromaticity is found in Morrison and Boyd, OrganicChemistry, (5th Ed., 1987), Chapter 13, entitled “ Aromaticity,” pages477-497, incorporated herein by reference. The term “aromatic group” isinclusive of both aryl and heteroaryl groups.

The term “aryl” as used herein is a group that contains any carbon-basedaromatic group including, but not limited to, benzene, naphthalene,phenyl, biphenyl, anthracene, and the like. The aryl group can besubstituted or unsubstituted. The aryl group can be substituted with oneor more groups including, but not limited to, alkyl, cycloalkyl, alkoxy,alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl,aldehyde, —NH₂, carboxylic acid, ester, ether, halide, hydroxy, ketone,azide, nitro, silyl, sulfo-oxo, or thiol as described herein. The term“biaryl” is a specific type of aryl group and is included in thedefinition of “aryl.” In addition, the aryl group can be a single ringstructure or comprise multiple ring structures that are either fusedring structures or attached via one or more bridging groups such as acarbon-carbon bond. For example, biaryl to two aryl groups that arebound together via a fused ring structure, as in naphthalene, or areattached via one or more carbon-carbon bonds, as in biphenyl.

The terms “amine” or “amino” as used herein are represented by theformula —NA¹A², where A¹ and A² can be, independently, hydrogen oralkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl,or heteroaryl group as described herein. A specific example of amino is—NH₂.

The term “carboxylic acid” as used herein is represented by the formula—C(O)OH or —(C═O)OH.

The term “ester” as used herein is represented by the formula —OC(O)A¹,—C(O)OA¹, or —(C═O)OA¹, where A¹ can be alkyl, cycloalkyl, alkenyl,cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group asdescribed herein. The term “polyester” as used herein is represented bythe formula —(A¹O(O)C—A²—C(O)O)_(a)— or —(A¹O(O)C—A²—OC(O))_(a)—, whereA¹ and A² can be, independently, an alkyl, cycloalkyl, alkenyl,cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group describedherein and “a” is an integer from 1 to 500. “Polyester” is as the termused to describe a group that is produced by the reaction between acompound having at least two carboxylic acid groups with a compoundhaving at least two hydroxyl groups.

The term “heteroaryl” as used herein refers to an aromatic group thathas at least one heteroatom incorporated within the ring of the aromaticgroup. Examples of heteroatoms include, but are not limited to,nitrogen, oxygen, sulfur, and phosphorus, where N-oxides, sulfur oxides,and dioxides are permissible heteroatom substitutions. The heteroarylgroup can be substituted or unsubstituted. The heteroaryl group can besubstituted with one or more groups including, but not limited to,alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl,sulfo-oxo, or thiol as described herein. Heteroaryl groups can bemonocyclic, or alternatively fused ring systems. Heteroaryl groupsinclude, but are not limited to, furyl, imidazolyl, pyrimidinyl,tetrazolyl, thienyl, pyridinyl, pyrrolyl, N-methylpyrrolyl, quinolinyl,isoquinolinyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl,oxadiazolyl, thiadiazolyl, isothiazolyl, pyridazinyl, pyrazinyl,benzofuranyl, benzodioxolyl, benzothiophenyl, indolyl, indazolyl,benzimidazolyl, imidazopyridinyl, pyrazolopyridinyl, andpyrazolopyrimidinyl. Further not limiting examples of heteroaryl groupsinclude, but are not limited to, pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, thiophenyl, pyrazolyl, imidazolyl, benzo[d]oxazolyl,benzo[d]thiazolyl, quinolinyl, quinazolinyl, indazolyl,imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl,benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazolyl, andpyrido[2,3-b]pyrazinyl.

The term “nitrile” or “cyano” as used herein is represented by theformula —CN.

The term “silyl” as used herein is represented by the formula —SiA¹A²A³,where A¹, A², and A³ can be, independently, hydrogen or an alkyl,cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl,or heteroaryl group as described herein.

The term “sulfo-oxo” as used herein is represented by the formulas—S(O)A¹, —S(O)₂A¹, —OS(O)₂A¹, or —OS(O)₂OA¹, where A¹ can be hydrogen oran alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl,aryl, or heteroaryl group as described herein. Throughout thisspecification “S(O)” is a short hand notation for S═O. The term“sulfonyl” is used herein to refer to the sulfo-oxo group represented bythe formula —S(O)₂A¹, where A¹ can be hydrogen or an alkyl, cycloalkyl,alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl groupas described herein. The term “sulfone” as used herein is represented bythe formula A¹S(O)₂A², where A¹ and A² can be, independently, an alkyl,cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, orheteroaryl group as described herein. The term “sulfoxide” as usedherein is represented by the formula A¹S(O)A², where A¹ and A² can be,independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl,cycloalkynyl, aryl, or heteroaryl group as described herein.

“R¹,” “R²,” “R³,” . . . “R^(n),” where n is an integer, as used hereincan, independently, possess one or more of the groups listed above. Forexample, if R¹ is a straight chain alkyl group, one of the hydrogenatoms of the alkyl group can optionally be substituted with a hydroxylgroup, an alkoxy group, an alkyl group, a halide, and the like.Depending upon the groups that are selected, a first group can beincorporated within second group or, alternatively, the first group canbe pendant (i.e., attached) to the second group. For example, with thephrase “an alkyl group comprising an amino group,” the amino group canbe incorporated within the backbone of the alkyl group. Alternatively,the amino group can be attached to the backbone of the alkyl group. Thenature of the group(s) that is (are) selected will determine if thefirst group is embedded or attached to the second group.

As described herein, compounds of the disclosure may contain “optionallysubstituted” moieties. In general, the term “substituted,” whetherpreceded by the term “optionally” or not, means that one or morehydrogens of the designated moiety are replaced with a suitablesubstituent. Unless otherwise indicated, an “optionally substituted”group may have a suitable substituent at each substitutable position ofthe group, and when more than one position in any given structure may besubstituted with more than one substituent selected from a specifiedgroup, the substituent may be either the same or different at everyposition. Combinations of substituents envisioned by this disclosure arepreferably those that result in the formation of stable or chemicallyfeasible compounds. In is also contemplated that, in certain aspects,unless expressly indicated to the contrary, individual substituents canbe further optionally substituted (i.e., further substituted orunsubstituted).

The term “stable,” as used herein, refers to compounds that are notsubstantially altered when subjected to conditions to allow for theirproduction, detection, and, in certain aspects, their recovery,purification, and use for one or more of the purposes disclosed herein.

Suitable monovalent substituents on a substitutable carbon atom of an“optionally substituted” group are independently halogen; —(CH₂)₀₋₄R°;—(CH₂)₀₋₄OR°; —O(CH₂)₀₋₄R°, —O—(CH₂)₀₋₄C(O)OR°; —(CH₂)₀₋₄CH(OR°)₂;—(CH₂)₀₋₄SR°; —(CH₂)₀₋₄Ph, which may be substituted with R°;—(CH₂)₀₋₄O(CH₂)₀₋₁Ph which may be substituted with R°; —CH═CHPh, whichmay be substituted with R°; —(CH₂)₀₋₄O(CH₂)₀₋₁-pyridyl which may besubstituted with R°; —NO₂; —CN; —N₃; —(CH₂)₀₋₄N(R°)₂;—(CH₂)₀₋₄N(R°)C(O)R°; —N(R°)C(S)R°; —(CH₂)₀₋₄N(R°)C(O)NR°₂;—N(R°)C(S)NR°₂; —(CH₂)₀₋₄N(R°)C(O)OR°; —N(R°)N(R°)C(O)R°;—N(R°)N(R°)C(O)NR°₂; —N(R°)N(R°)C(O)OR°; —(CH₂)₀₋₄C(O)R°; —C(S)R°;—(CH₂)₀₋₄C(O)OR°; —(CH₂)₀₋₄C(O)SR°; —(CH₂)₀₋₄C(O)OSiR°₃;—(CH₂)₀₋₄OC(O)R°; —OC(O)(CH₂)₀₋₄SR—; SC(S)SR°; —(CH₂)₀₋₄SC(O)R°;—(CH₂)₀₋₄C(O)NR°₂; —C(S)NR°₂; —C(S)SR°; —(CH₂)₀₋₄OC(O)NR°₂;—C(O)N(OR°)R°; —C(O)C(O)R°; —C(O)CH₂C(O)R°; —C(NOR°)R°; —(CH₂)₀₋₄SSR°;—(CH₂)₀₋₄S(O)₂R°; —(CH₂)₀₋₄S(O)₂OR°; —(CH₂)₀₋₄OS(O)₂R°; —S(O)₂NR°₂;—(CH₂)₀₋₄S(O)R°; —N(R°)S(O)₂NR°₂; —N(R°)S(O)₂R°; —N(OR°)R°; —C(NH)NR°₂;—P(O)₂R°; —P(O)R°₂; —OP(O)R°₂; —OP(O)(OR°)₂; SiR°₃; —(C₁₋₄ straight orbranched alkylene)O—N(R°)₂; or —(C₁₋₄ straight or branchedalkylene)C(O)O—N(R°)₂, wherein each R° may be substituted as definedbelow and is independently hydrogen, C₁₋₆ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, —CH₂-(5-6 membered heteroaryl ring), or a 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences of R°,taken together with their intervening atom(s), form a 3-12-memberedsaturated, partially unsaturated, or aryl mono- or bicyclic ring having0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur,which may be substituted as defined below.

Suitable monovalent substituents on R° (or the ring formed by taking twoindependent occurrences of R° together with their intervening atoms),are independently halogen, —(CH₂)₀₋₂R^(•); —(haloR^(•)), —(CH₂)₀₋₂OH,—(CH₂)₀₋₂OR^(•); —(CH₂)₀₋₂CH(OR^(•))₂; —O(haloR^(•)), —CN, —N₃,—(CH₂)₀₋₂C(O)R^(•), —(CH₂)₀₋₂C(O)OH, —(CH₂)₀₋₂C(O)OR^(•),—(CH₂)₀₋₂SR^(•), —(CH₂)₀₋₂SH, —(CH₂)₀₋₂NH₂, —(CH₂)₀₋₂NHR^(•),—(CH₂)₀₋₂NR^(•) ₂, —NO₂, —SiR^(•) ₃, —OSiR^(•) ₃, —C(O)SR^(•), —(C₁₋₄straight or branched alkylene)C(O)OR^(•), or —SSR^(•) wherein each R^(•)is unsubstituted or where preceded by “halo” is substituted only withone or more halogens, and is independently selected from C₁₋₄ aliphatic,—CH₂Ph, —O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur. Suitable divalent substituents on asaturated carbon atom of R° include ═O and ═S.

Suitable divalent substituents on a saturated carbon atom of an“optionally substituted” group include the following: ═O, ═S, ═NNR*₂,═NNHC(O)R*, ═NNHC(O)OR*, ═NNHS(O)₂R*, ═NR*, ═NOR*, —O(C(R*₂))₂₋₃O—, or—S(C(R*₂))₂₋₃S—, wherein each independent occurrence of R* is selectedfrom hydrogen, C₁₋₆ aliphatic which may be substituted as defined below,or an unsubstituted 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur. Suitable divalent substituents that are bound tovicinal substitutable carbons of an “optionally substituted” groupinclude: —O(CR*₂)₂₋₃O—, wherein each independent occurrence of R* isselected from hydrogen, C₁₋₆ aliphatic which may be substituted asdefined below, or an unsubstituted 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R* include halogen,—R^(•), —(haloR^(•)), —OH, —OR^(•), —O(haloR^(•)), —CN, —C(O)OH,—C(O)OR^(•), —NH₂, —NHR^(•), —NR^(•) ₂, or —NO₂, wherein each R^(•) isunsubstituted or where preceded by “halo” is substituted only with oneor more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

Suitable substituents on a substitutable nitrogen of an “optionallysubstituted” group include —R^(†), —NR^(†) ₂, —C(O)R^(†), —C(O)OR^(†),—C(O)C(O)R^(†), —C(O)CH₂C(O)R^(†), —S(O)₂R^(†), —S(O)₂NR^(†) ₂,—C(S)NR^(†) ₂, —C(NH)NR^(†) ₂, or —N(R^(†))S(O)₂R^(†); wherein eachR^(†) is independently hydrogen, C₁₋₆ aliphatic which may be substitutedas defined below, unsubstituted —OPh, or an unsubstituted 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(†), taken together with their intervening atom(s) form anunsubstituted 3-12-membered saturated, partially unsaturated, or arylmono- or bicyclic ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R^(†) are independentlyhalogen,—R^(•), —(haloR^(•)), —OH, —OR^(•), —O(haloR^(•)), —CN, —C(O)OH,—C(O)OR^(•), —NH₂, —NHR^(•), —NR^(•) ₂, or —NO₂, wherein each R^(•) isunsubstituted or where preceded by “halo” is substituted only with oneor more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

The term “organic residue” defines a carbon containing residue, i.e., aresidue comprising at least one carbon atom, and includes but is notlimited to the carbon-containing groups, residues, or radicals definedhereinabove. Organic residues can contain various heteroatoms, or bebonded to another molecule through a heteroatom, including oxygen,nitrogen, sulfur, phosphorus, or the like. Examples of organic residuesinclude but are not limited alkyl or substituted alkyls, alkoxy orsubstituted alkoxy, mono or di-substituted amino, amide groups, etc.Organic residues can preferably comprise 1 to 18 carbon atoms, 1 to 15,carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbonatoms, or 1 to 4 carbon atoms. In a further aspect, an organic residuecan comprise 2 to 18 carbon atoms, 2 to 15, carbon atoms, 2 to 12 carbonatoms, 2 to 8 carbon atoms, 2 to 4 carbon atoms, or 2 to 4 carbon atoms.

A very close synonym of the term “residue” is the term “radical,” whichas used in the specification and concluding claims, refers to afragment, group, or substructure of a molecule described herein,regardless of how the molecule is prepared. For example, a2,4-thiazolidinedione radical in a particular compound has thestructure:

regardless of whether thiazolidinedione is used to prepare the compound.In some embodiments the radical (for example an alkyl) can be furthermodified (i.e., substituted alkyl) by having bonded thereto one or more“substituent radicals.” The number of atoms in a given radical is notcritical to the present disclosure unless it is indicated to thecontrary elsewhere herein.

“Organic radicals,” as the term is defined and used herein, contain oneor more carbon atoms. An organic radical can have, for example, 1-26carbon atoms, 1-18 carbon atoms, 1-12 carbon atoms, 1-8 carbon atoms,1-6 carbon atoms, or 1-4 carbon atoms. In a further aspect, an organicradical can have 2-26 carbon atoms, 2-18 carbon atoms, 2-12 carbonatoms, 2-8 carbon atoms, 2-6 carbon atoms, or 2-4 carbon atoms. Organicradicals often have hydrogen bound to at least some of the carbon atomsof the organic radical. One example, of an organic radical thatcomprises no inorganic atoms is a 5, 6, 7, 8-tetrahydro-2-naphthylradical. In some embodiments, an organic radical can contain 1-10inorganic heteroatoms bound thereto or therein, including halogens,oxygen, sulfur, nitrogen, phosphorus, and the like. Examples of organicradicals include but are not limited to an alkyl, substituted alkyl,cycloalkyl, substituted cycloalkyl, mono-substituted amino,di-substituted amino, acyloxy, cyano, carboxy, carboalkoxy,alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide,substituted dialkylcarboxamide, alkylsulfonyl, alkylsulfinyl, thioalkyl,thiohaloalkyl, alkoxy, substituted alkoxy, haloalkyl, haloalkoxy, aryl,substituted aryl, heteroaryl, heterocyclic, or substituted heterocyclicradicals, wherein the terms are defined elsewhere herein. A fewnon-limiting examples of organic radicals that include heteroatomsinclude alkoxy radicals, trifluoromethoxy radicals, acetoxy radicals,dimethylamino radicals and the like.

As used herein, the term “derivative” refers to a compound having astructure derived from the structure of a parent compound (e.g., acompound disclosed herein) and whose structure is sufficiently similarto those disclosed herein and based upon that similarity, would beexpected by one skilled in the art to exhibit the same or similaractivities and utilities as the claimed compounds, or to induce, as aprecursor, the same or similar activities and utilities as the claimedcompounds. Exemplary derivatives include salts, esters, amides, salts ofesters or amides, and N-oxides of a parent compound.

Compounds described herein can contain one or more double bonds and,thus, potentially give rise to cis/trans (E/Z) isomers, as well as otherconformational isomers. Unless stated to the contrary, the disclosureincludes all such possible isomers, as well as mixtures of such isomers.

Unless stated to the contrary, a formula with chemical bonds shown onlyas solid lines and not as wedges or dashed lines contemplates eachpossible isomer, e.g., each enantiomer and diastereomer, and a mixtureof isomers, such as a racemic or scalemic mixture. Compounds describedherein can contain one or more asymmetric centers and, thus, potentiallygive rise to diastereomers and optical isomers. Unless stated to thecontrary, the present disclosure includes all such possiblediastereomers as well as their racemic mixtures, their substantiallypure resolved enantiomers, all possible geometric isomers, andpharmaceutically acceptable salts thereof. Mixtures of stereoisomers, aswell as isolated specific stereoisomers, are also included. During thecourse of the synthetic procedures used to prepare such compounds, or inusing racemization or epimerization procedures known to those skilled inthe art, the products of such procedures can be a mixture ofstereoisomers.

Many organic compounds exist in optically active forms having theability to rotate the plane of plane-polarized light. In describing anoptically active compound, the prefixes D and L or R and S are used todenote the absolute configuration of the molecule about its chiralcenter(s). The prefixes d and I or (+) and (−) are employed to designatethe sign of rotation of plane-polarized light by the compound, with (−)or meaning that the compound is levorotatory. A compound prefixed with(+) or d is dextrorotatory. For a given chemical structure, thesecompounds, called stereoisomers, are identical except that they arenon-superimposable mirror images of one another. A specific stereoisomercan also be referred to as an enantiomer, and a mixture of such isomersis often called an enantiomeric mixture. A 50:50 mixture of enantiomersis referred to as a racemic mixture. Many of the compounds describedherein can have one or more chiral centers and therefore can exist indifferent enantiomeric forms. If desired, a chiral carbon can bedesignated with an asterisk (*). When bonds to the chiral carbon aredepicted as straight lines in the disclosed formulas, it is understoodthat both the (R) and (S) configurations of the chiral carbon, and henceboth enantiomers and mixtures thereof, are embraced within the formula.As is used in the art, when it is desired to specify the absoluteconfiguration about a chiral carbon, one of the bonds to the chiralcarbon can be depicted as a wedge (bonds to atoms above the plane) andthe other can be depicted as a series or wedge of short parallel linesis (bonds to atoms below the plane). The Cahn-Inglod -Prelog system canbe used to assign the (R) or (S) configuration to a chiral carbon.

Compounds described herein comprise atoms in both their natural isotopicabundance and in non-natural abundance. The disclosed compounds can beisotopically -labeled or isotopically-substituted compounds identical tothose described, but for the fact that one or more atoms are replaced byan atom having an atomic mass or mass number different from the atomicmass or mass number typically found in nature. Examples of isotopes thatcan be incorporated into compounds of the disclosure include isotopes ofhydrogen, carbon, nitrogen, oxygen, sulfur, fluorine and chlorine, suchas ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³⁵S, ¹⁸F, and ³⁶Cl, respectively.Compounds further comprise prodrugs thereof and pharmaceuticallyacceptable salts of said compounds or of said prodrugs which contain theaforementioned isotopes and/or other isotopes of other atoms are withinthe scope of this disclosure. Certain isotopically-labeled compounds ofthe present disclosure, for example those into which radioactiveisotopes such as ³H and ¹⁴C are incorporated, are useful in drug and/orsubstrate tissue distribution assays. Tritiated, i.e., ³H, andcarbon-14, i.e., ¹⁴C, isotopes are particularly preferred for their easeof preparation and detectability. Further, substitution with heavierisotopes such as deuterium, i.e., ²H, can afford certain therapeuticadvantages resulting from greater metabolic stability, for exampleincreased in vivo half-life or reduced dosage requirements and, hence,may be preferred in some circumstances. Isotopically labeled compoundsof the present disclosure and prodrugs thereof can generally be preparedby carrying out the procedures below, by substituting a readilyavailable isotopically labeled reagent for a non- isotopically labeledreagent.

The compounds described in the disclosure can be present as a solvate.In some cases, the solvent used to prepare the solvate is an aqueoussolution, and the solvate is then often referred to as a hydrate. Thecompounds can be present as a hydrate, which can be obtained, forexample, by crystallization from a solvent or from aqueous solution. Inthis connection, one, two, three or any arbitrary number of solvent orwater molecules can combine with the compounds according to thedisclosure to form solvates and hydrates. Unless stated to the contrary,the disclosure includes all such possible solvates.

The term “co-crystal” means a physical association of two or moremolecules which owe their stability through non-covalent interaction.One or more components of this molecular complex provide a stableframework in the crystalline lattice. In certain instances, the guestmolecules are incorporated in the crystalline lattice as anhydrates orsolvates, see e.g. “Crystal Engineering of the Composition ofPharmaceutical Phases. Do Pharmaceutical Co-crystals Represent a NewPath to Improved Medicines?” Almarasson, O., et al., The Royal Societyof Chemistry, 1889-1896, 2004. Examples of co-crystals includep-toluenesulfonic acid and benzenesulfonic acid.

It is known that chemical substances form solids which are present indifferent states of order which are termed polymorphic forms ormodifications. The different modifications of a polymorphic substancecan differ greatly in their physical properties. The compounds accordingto the disclosure can be present in different polymorphic forms, with itbeing possible for particular modifications to be metastable. Unlessstated to the contrary, the disclosure includes all such possiblepolymorphic forms.

In some aspects, a structure of a compound can be represented by aformula:

which is understood to be equivalent to a formula:

wherein n is typically an integer. That is, R^(n) is understood torepresent five independent substituents, R^(n(a)), R^(n(b)), R^(n(c)),R^(n(d)), and R^(n(e)). By “independent substituents,” it is meant thateach R substituent can be independently defined. For example, if in oneinstance R^(n(a)) is halogen, then R^(n(b)) is not necessarily halogenin that instance.

Certain materials, compounds, compositions, and components disclosedherein can be obtained commercially or readily synthesized usingtechniques generally known to those of skill in the art. For example,the starting materials and reagents used in preparing the disclosedcompounds and compositions are either available from commercialsuppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), AcrosOrganics (Morris Plains, N.J.), Fisher Scientific (Pittsburgh, Pa.), orSigma (St. Louis, Mo.) or are prepared by methods known to those skilledin the art following procedures set forth in references such as Fieserand Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wileyand Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 andSupplementals (Elsevier Science Publishers, 1989); Organic Reactions,Volumes 1-40 (John Wiley and Sons, 1991); March's Advanced OrganicChemistry, (John Wiley and Sons, 4th Edition); and Larock'sComprehensive Organic Transformations (VCH Publishers Inc., 1989).

Unless otherwise expressly stated, it is in no way intended that anymethod set forth herein be construed as requiring that its steps beperformed in a specific order. Accordingly, where a method claim doesnot actually recite an order to be followed by its steps or it is nototherwise specifically stated in the claims or descriptions that thesteps are to be limited to a specific order, it is no way intended thatan order be inferred, in any respect. This holds for any possiblenon-express basis for interpretation, including: matters of logic withrespect to arrangement of steps or operational flow; plain meaningderived from grammatical organization or punctuation; and the number ortype of embodiments described in the specification.

Disclosed are the components to be used to prepare the compositions ofthe disclosure as well as the compositions themselves to be used withinthe methods disclosed herein. These and other materials are disclosedherein, and it is understood that when combinations, subsets,interactions, groups, etc. of these materials are disclosed that whilespecific reference of each various individual and collectivecombinations and permutation of these compounds cannot be explicitlydisclosed, each is specifically contemplated and described herein. Forexample, if a particular compound is disclosed and discussed and anumber of modifications that can be made to a number of moleculesincluding the compounds are discussed, specifically contemplated is eachand every combination and permutation of the compound and themodifications that are possible unless specifically indicated to thecontrary. Thus, if a class of molecules A, B, and C are disclosed aswell as a class of molecules D, E, and F and an example of a combinationmolecule, A-D is disclosed, then even if each is not individuallyrecited each is individually and collectively contemplated meaningcombinations, A-E, A-F, B-D, B-E, B-F, C-D, C-E, and C-F are considereddisclosed. Likewise, any subset or combination of these is alsodisclosed. Thus, for example, the sub-group of A -E, B-F, and C-E wouldbe considered disclosed. This concept applies to all aspects of thisapplication including, but not limited to, steps in methods of makingand using the compositions of the disclosure. Thus, if there are avariety of additional steps that can be performed it is understood thateach of these additional steps can be performed with any specificembodiment or combination of embodiments of the methods of thedisclosure.

It is understood that the compositions disclosed herein have certainfunctions. Disclosed herein are certain structural requirements forperforming the disclosed functions, and it is understood that there area variety of structures that can perform the same function that arerelated to the disclosed structures, and that these structures willtypically achieve the same result.

B. Disclosed Compounds

In one aspect, the present disclosure relates to compounds that can beused as intermediates useful for the preparation of terpenoid cores. Ina further aspect, the disclosed methods pertain to the preparation ofcompounds comprising a terpenoid core or scaffold, such as 6/7/5tricycloalkanes. The disclosed methods utilize abundant startingmaterials and simple reaction sequences that can be used to tunably andscalably assemble common terpenoid cores. In various aspects, thepresent disclosure pertains to compounds prepared using the disclosedmethods.

1. Structure

In one aspect, the present disclosure relates to Knoevenagel adductshaving a formula represented by a structure:

wherein E is —CN or —(C═O)OR¹⁰; wherein R¹⁰ is C1-C6 alkyl; wherein eachof R^(1a), R^(1b), R^(1c), and R^(1d) is independently hydrogen, C1-C6alkyl, aryl, or —(CH₂)_(m)(C═O)OR¹¹; or wherein R^(1a) and R^(1c) arecovalently bonded and, together with more intermediate carbons, comprise—CH₂CH₂—, or —CH═CH—; wherein m is an integer selected from 0, 1, 2, and3; and wherein R¹¹ is C1-C6 alkyl; wherein A¹ is —C(R²⁰)(R²¹)—, —NR²²—or —CH₂—; wherein R²⁰ is hydrogen, C1-C6 alkyl, or —(CH₂)_(p)C═O)OR³⁰;wherein R³⁰ is C1-C6 alkyl; and wherein p is an integer selected from 0,1, 2, and 3; wherein R²¹ is hydrogen, C1-C6 alkyl, or—(CH₂)_(q)C═O)OR³¹; wherein R³¹ is C1-C6 alkyl; and wherein q is aninteger selected from 0, 1, 2, and 3; and wherein R²² is C1-C6 alkyl, or—(C═O)OR³²; and wherein R³² is C1-C6 alkyl.

In a further aspect, the Knoevenagel adduct has a formula represented bya structure:

or combinations thereof.

In a further aspect, the Knoevenagel adduct has a formula represented bya structure:

or combinations thereof.

In a further aspect, the Knoevenagel adduct has a formula represented bya structure:

or combinations thereof.

In a further aspect, the Knoevenagel adduct has a formula represented bya structure:

or combinations thereof.

In a further aspect, the Knoevenagel adduct has a formula represented bya structure:

or combinations thereof.

In a further aspect, the Knoevenagel adduct has a formula represented bya structure:

or cornbionations thereof.

In one aspect, the present disclosure relates to 1,5 enynes having aformula represented by a structure:

wherein E is —CN or —(C═O)OR¹⁰; wherein R¹⁰ is C1-C6 alkyl; wherein eachof R^(1a), R^(1b), R^(1c), and R^(1d) is independently hydrogen, C1-C6alkyl, aryl, or —(CH₂)_(m)(C═O)OR¹¹; or wherein R^(1a) and R^(1c) arecovalently bonded and, together with more intermediate carbons, comprise—CH₂CH₂—, or —CH═CH—; wherein m is an integer selected from 0, 1, 2, and3; and wherein R¹¹ is C1-C6 alkyl; wherein R² is hydrogen, C1-C6 alkyl,aryl, or —(CH₂)_(n)(C═O)OR¹²; wherein n is an integer selected from 0,1, 2, and 3; and wherein R¹² is C1-C6 alkyl; wherein A¹ is—C(R²⁰)(R²¹)—, —NR²²—or —CH₂—; wherein R²⁰ is hydrogen, C1-C6 alkyl, or—(CH₂)_(p)C═O)OR³⁰; wherein R³⁰ is C1-C6 alkyl; and wherein p is aninteger selected from 0, 1, 2, and 3; wherein R²¹ is hydrogen, C1-C6alkyl, or —(CH₂)_(q)C═O)OR³¹; wherein R³¹ is C1-C6 alkyl; and wherein qis an integer selected from 0, 1, 2, and 3; and wherein R²² is C1-C6alkyl, or —(C═O)OR³²; and wherein R³² is C1-C6 alkyl.

In one aspect, the present disclosure relates to 1,5 enynes having aformula represented by a structure:

or combinations thereof.

In one aspect, the present disclosure relates to 1,5 enynes having aformula represented by a structure:

or combinations thereof.

In one aspect, the present disclosure relates to 1,5 enynes having aformula represented by a structure:

or combinations thereof.

In one aspect, the present disclosure relates to 1,5 enynes having aformula represented by a structure:

or combinations thereof.

In one aspect, the present disclosure relates to 1,5 enynes having aformula represented by a structure:

or combinations thereof.

In one aspect, the present disclosure relates to 1,5 enynes having aformula represented by a structure:

or combinations thereof.

In one aspect, the present disclosure relates to γ-allenyl Knoevenageladducts having a formula represented by a structure:

wherein E is —CN or —(C═O)OR¹⁰; wherein R¹⁰ is C1-C6 alkyl; wherein eachof R^(1a), R^(1b), R^(1c), and R^(1d) is independently hydrogen, C1-C6alkyl, aryl, or —(CH₂)_(m)(C═O)OR¹¹; or wherein R^(1a) and R^(1c) arecovalently bonded and, together with more intermediate carbons, comprise—CH₂CH₂—, or —CH═CH—; wherein m is an integer selected from 0, 1, 2, and3; and wherein R¹¹ is C1-C6 alkyl; wherein R² is hydrogen, C1-C6 alkyl,aryl, or —(CH₂)_(n)(C═O)OR¹²; wherein n is an integer selected from 0,1, 2, and 3; and wherein R¹² is C1-C6 alkyl; wherein A¹ is—C(R²⁰)(R²¹)—, —NR²²—or —CH₂—; wherein R²⁰ is hydrogen, C1-C6 alkyl, or—(CH₂)_(p)C═O)OR³⁰; wherein R³⁰ is C1-C6 alkyl; and wherein p is aninteger selected from 0, 1, 2, and 3; wherein R²¹ is hydrogen, C1-C6alkyl, or —(CH₂)_(q)C═O)OR³¹; wherein R³¹ is C1-C6 alkyl; and wherein qis an integer selected from 0, 1, 2, and 3; and wherein R²² is C1-C6alkyl, or —(C═O)OR³²; and wherein R³² is C1-C6 alkyl.

In one aspect, the present disclosure relates to γ-allenyl Knoevenageladducts having a formula represented by a structure:

or combinations thereof.

In one aspect, the present disclosure relates to γ-allenyl Knoevenageladducts having a formula represented by a structure:

or combinations thereof.

In one aspect, the present disclosure relates to γ-allenyl Knoevenageladducts having a formula represented by a structure:

or combinations thereof.

In one aspect, the present disclosure relates to γ-allenyl Knoevenageladducts having a formula represented by a structure:

or combinations thereof.

In one aspect, the present disclosure relates to γ-allenyl Knoevenageladducts having a formula represented by a structure:

or combinations thereof.

In one aspect, the present disclosure relates to γ-allenyl Knoevenageladducts having a formula represented by a structure:

or combinations thereof.

In one aspect, the present disclosure relates to propargyl electrophileshaving a formula represented by a structure:

wherein R³ is hydrogen, C1-C6 alkyl, aryl, trimethylsilyl, or—(CH₂)_(r)(C═O)OR¹⁵; wherein r is an integer selected from 0, 1, 2, and3; and wherein R¹⁵ is C1-C6 alkyl.

In one aspect, the present disclosure relates to allenyne precursors toa terpenoid scaffold; wherein the allenyne precursor to the terpenoidscaffold has a formula represented by a structure:

wherein E is —CN or —(C═O)OR¹⁰; wherein R¹⁰ is C1-C6 alkyl; wherein eachof R^(1a), R^(1b), R^(1c), and R^(1d) is independently hydrogen, C1-C6alkyl, aryl, or —(CH₂)_(m)(C═O)OR¹¹; or wherein R^(1a) and R^(1c) arecovalently bonded and, together with more intermediate carbons, comprise—CH₂CH₂—, or —CH═CH—; wherein m is an integer selected from 0, 1, 2, and3; and wherein R¹¹ is C1-C6 alkyl; wherein R² is hydrogen, C1-C6 alkyl,aryl, or —(CH₂)_(n)(C═O)OR¹²; wherein n is an integer selected from 0,1, 2, and 3; and wherein R¹² is C1-C6 alkyl; wherein A¹ is—C(R²⁰)(R²¹)—, —NR²²—or —CH₂—; wherein R²⁰ is hydrogen, C1-C6 alkyl, or—(CH₂)_(p)C═O)OR³⁰; wherein R³⁰ is C1-C6 alkyl; and wherein p is aninteger selected from 0, 1, 2, and 3; wherein R²¹ is hydrogen, C1-C6alkyl, or —(CH₂)_(q)C═O)OR³¹; wherein R³¹ is C1-C6 alkyl; and wherein qis an integer selected from 0, 1, 2, and 3; and wherein R²² is C1-C6alkyl, or —(C═O)OR³²; and wherein R³² is C1-C6 alkyl; and wherein R³ ishydrogen, C1-C6 alkyl, aryl, trimethylsilyl, or —(CH₂)_(r)(C═O)OR¹⁵;wherein r is an integer selected from 0, 1, 2, and 3; and wherein R¹⁵ isC1-C6 alkyl.

In one aspect, the present disclosure relates to allenyne precursors toa terpenoid scaffold; wherein the allenyne precursor to the terpenoidscaffold has a formula represented by a structure:

or combinations thereof.

In one aspect, the present disclosure relates to allenyne precursors toa terpenoid scaffold; wherein the allenyne precursor to the terpenoidscaffold has a formula represented by a structure:

or combinations thereof.

In one aspect, the present disclosure relates to allenyne precursors toa terpenoid scaffold; wherein the allenyne precursor to the terpenoidscaffold has a formula represented by a structure:

or combinations thereof.

In one aspect, the present disclosure relates to allenyne precursors toa terpenoid scaffold; wherein the allenyne precursor to the terpenoidscaffold has a formula represented by a structure:

or combinations thereof.

In one aspect, the present disclosure relates to allenyne precursors toa terpenoid scaffold; wherein the allenyne precursor to the terpenoidscaffold has a formula represented by a structure:

or combinations thereof.

In one aspect, the present disclosure relates to allenyne precursors toa terpenoid scaffold; wherein the allenyne precursor to the terpenoidscaffold has a formula represented by a structure:

or combinations thereof.

In one aspect, the present disclosure relates to terpenoid scaffoldshaving a formula represented by a structure:

wherein E is —CN or —(C═O)OR¹⁰; wherein R¹⁰ is C1-C6 alkyl; wherein eachof R^(1a), R^(1b), R^(1c), and R^(1d) is independently hydrogen, C1-C6alkyl, aryl, or —(CH₂)_(m)(C═O)OR¹¹; or wherein R^(1a) and R^(1c) arecovalently bonded and, together with more intermediate carbons, comprise—CH₂CH₂—, or —CH═CH—; wherein m is an integer selected from 0, 1, 2, and3; and wherein R¹¹ is C1-C6 alkyl; wherein R² is hydrogen, C1-C6 alkyl,aryl, or —(CH₂)_(n)(C═O)OR¹²; wherein n is an integer selected from 0,1, 2, and 3; and wherein R¹² is C1-C6 alkyl; wherein A¹ is—C(R²⁰)(R²¹)—, —NR²²—or —CH₂—; wherein R²⁰ is hydrogen, C1-C6 alkyl, or—(CH₂)_(p)C═O)OR³⁰; wherein R³⁰ is C1-C6 alkyl; and wherein p is aninteger selected from 0, 1, 2, and 3; wherein R²¹ is hydrogen, C1-C6alkyl, or —(CH₂)_(q)C═O)OR³⁰; wherein R³¹ is C1-C6 alkyl; and wherein qis an integer selected from 0, 1, 2, and 3; and wherein R²² is C1-C6alkyl, or —(C═O)OR³²; and wherein R³² is C1-C6 alkyl; and wherein R³ ishydrogen, C1-C6 alkyl, aryl, trimethylsilyl, or —(CH₂)_(r)(C═O)OR¹⁵;wherein r is an integer selected from 0, 1, 2, and 3; and wherein R¹⁵ isC1-C6 alkyl.

In one aspect, the present disclosure relates to terpenoid scaffoldshaving a formula represented by a structure:

or combinations thereof.

In one aspect, the present disclosure relates to terpenoid scaffoldshaving a formula represented by a structure:

or combinations thereof.

In one aspect, the present disclosure relates to terpenoid scaffoldshaving a formula represented by a structure:

or combinations thereof.

In one aspect, the present disclosure relates to terpenoid scaffoldshaving a formula represented by a structure:

or combinations thereof.

In one aspect, the present disclosure relates to terpenoid scaffoldshaving a formula represented by a structure:

or combinations thereof.

In one aspect, the present disclosure relates to terpenoid scaffoldshaving a formula represented by a structure:

or combinations thereof.

2. A¹ Group.

In one aspect, A¹ is —C(R²⁰)(R²¹)—, —NR²²— or —CH₂—; R²⁰ is hydrogen,C1-C6 alkyl, or —(CH₂)_(p)C═O)OR³⁰; wherein R³⁰ is C1-C6 alkyl; andwherein p is an integer selected from 0, 1, 2, and 3; R²¹ is hydrogen,C1-C6 alkyl, or —(CH₂)_(q)C═O)OR³¹; wherein R³¹ is C1-C6 alkyl; andwherein q is an integer selected from 0, 1, 2, and 3; and R²² is C1-C6alkyl, or —(C═O)OR³²; and wherein R³² is C1-C6 alkyl. In a furtheraspect, A¹ is —C(R²⁰)(R²¹)—, —NR²²—or —CH₂—; R²⁰ is hydrogen, C1-C6alkyl, or —(CH₂)_(p)C═O)OR³⁰; wherein R³⁰ is C1-C6 alkyl; and wherein pis an integer selected from 0, 1, and 2; R²¹ is hydrogen, C1-C6 alkyl,or —(CH₂)_(q)C═O)OR³¹; wherein R³¹ is C1-C6 alkyl; and wherein q is aninteger selected from 0, 1, and 2; and R²² is C1-C6 alkyl, or—(C═O)OR³²; and wherein R³² is C1-C6 alkyl. In a still further aspect,A¹ is —C(R²⁰)(R²¹)—, —NR²²— or —CH₂—; R²⁰ is hydrogen, C1-C6 alkyl, or—(CH₂)_(p)C═O)OR³⁰; wherein R³⁰ is C1-C6 alkyl; and wherein p is aninteger selected from 0 and 1; R²¹ is hydrogen, C1-C6 alkyl, or—(CH₂)_(q)C═O)OR³¹; wherein R³¹ is C1-C6 alkyl; and wherein q is aninteger selected from 0 and 1; and R²² is C1-C6 alkyl, or —(C═O)OR³²;and wherein R³² is C1-C6 alkyl. In a yet further aspect, A¹ is—C(R²⁰)(R²¹)—, —NR²²— or —CH₂—; R²⁰ is hydrogen, C1-C6 alkyl, or—(CH₂)₂(C═O)OR³⁰; wherein R³⁰ is C1-C6 alkyl; R²¹ is hydrogen, C1-C6alkyl, or —(CH₂)₂(C═O)OR³¹; wherein R³¹ is C1-C6 alkyl; and wherein q isan integer selected from 0, 1, 2, and 3; and R²² is C1-C6 alkyl, or—(C═O)OR³²; and wherein R³² is C1-C6 alkyl. In an even further aspect,A¹ is —C(R²⁰)(R²¹)—, —NR²²— or —CH₂—; R²⁰ is hydrogen, C1-C6 alkyl, or—(CH₂)(C═O)OR³⁰; wherein R³⁰ is C1-C6 alkyl; R²¹ is hydrogen, C1-C6alkyl, or —(CH₂)(C═O)OR³¹; wherein R³¹ is C1-C6 alkyl; and wherein q isan integer selected from 0, 1, 2, and 3; and R²² is C1-C6 alkyl, or—(C═O)OR³²; and wherein R³² is C1-C6 alkyl.

In a further aspect, A¹ is —CH₂—, —CH(CH₃)—, —C(CH₃)₂—, —CH(CH₂CH₃)—,—CH(CH₂)(C═O)OCH₃, —CH(CH₂)(C═O)OCH₂CH₃, —CH(CH₂)(C═O)O(CH₂)₂CH₃,—CH(CH₂)(C═O)OCH(CH₃)₂, —CH(CH₂)(C═O)O(CH₂)₃CH₃, —CH(C═O)OCH₃,—CH(C═O)OCH₂CH₃, —CH(C═O)O(CH₂)₂CH₃, —CH(C═O)OCH(CH₃)₂, or—CH(C═O)O(CH₂)₃CH₃, or —NBoc—. In a still further aspect, A¹ is —CH₂—,—CH(CH₃)—, —CH(CH₂CH₃)—, —CH(CH₂)(C═O)OCH₃, —CH(CH₂)(C═O)OCH₂CH₃,—CH(C═O)OCH₃, —CH(C═O)OCH₂CH₃, —CH(C═O)O(CH₂)₂CH₃, or —NBoc—. In a yetfurther aspect, A¹ is —CH₂—, —CH(CH₃)—, —CH(CH₂)(C═O)OCH₃, —CH(C═O)OCH₃,or —NBoc—. In an even further aspect, A¹ is —CH₂—, —CH(CH₃)—,—CH(CH₂)(C═O)OCH₃, —CH(C═O)OCH₃, or —NBoc—.

In a further aspect, A¹ is —CH₂—, —CH(CH₃)—, —C(CH₃)₂—, or —CH(CH₂CH₃)—.In a still further aspect, A¹ is —CH₂—, —CH(CH₃)—, or —CH(CH₂CH₃)—. In ayet further aspect, A¹ is —CH₂—or —CH(CH₃)—. In an even further aspect,A¹ is —CH₂—. In a still further aspect, A¹ is —CH(CH₃)—.

In a further aspect, A¹ is —NBoc—.

3. E Group.

In one aspect, E is —CN or —(C═O)OR¹⁰. In a further aspect, E is CN. Ina still further aspect, E is —(C═O)OR¹⁰. In a yet further aspect, E is—(C═O)OCH₃, —(C═O)OCH₂CH₃, —(C═O)O(CH₂)₂CH₃, —(C═O)OCH(CH₃)₂, or—(C═O)O(CH₂)₃CH₃. In an even further aspect, E is —(C═O)OCH₃ or—(C═O)OCH₂CH₃. In various further aspects, E is CN, —(C═O)OCH₃,—(C═O)OCH₂CH₃, —(C═O)O(CH₂)₂CH₃, —(C═O)OCH(CH₃)₂, or —(C═O)O(CH₂)₃CH₃.In a further aspect, E is CN, —(C═O)OCH₃, or —(C═O)OCH₂CH₃. In a yetfurther aspect, E is CN or —(C═O)OCH₃.

4. R^(1A), R^(1B), R^(1C), and R^(1D) Groups.

In one aspect, each of R^(1a), R^(1b), R^(1c), and R^(1d) isindependently hydrogen, C1-C6 alkyl, aryl, or —(CH₂)_(m)(C═O)OR¹¹; R¹¹is C1-C6 alkyl; and m is an integer selected from 0, 1, 2, and 3; orR^(1a) and R^(1c) are covalently bonded and, together with moreintermediate carbons, comprise —CH₂CH₂—, or —CH═CH—. In a furtheraspect, each of R^(1a), R^(1b), R^(1c), and R^(1d) is independentlyhydrogen, C1-C6 alkyl, aryl, or —(CH₂)_(m)(C═O)OR¹¹; R¹¹ is C1-C6 alkyl;and m is an integer selected from 0, 1, and 2; or R^(1a) and R^(1c) arecovalently bonded and, together with more intermediate carbons, comprise—CH₂CH₂—, or —CH═CH—. In a still further aspect, each of R^(1a), R^(1b),R^(1c), and R^(1d) is independently hydrogen, C1-C6 alkyl, aryl, or—(CH₂)_(m)(C═O)OR¹¹; R¹¹ is C1-C6 alkyl; and m is an integer selectedfrom 0 and 1; or R^(1a) and R^(1c) are covalently bonded and, togetherwith more intermediate carbons, comprise —CH₂CH₂—, or —CH═CH—. In aneven further aspect, each of R^(1a), R^(1b), R^(1c), and R^(1d) isindependently hydrogen, C1-C6 alkyl, aryl, or —(CH₂)(C═O)OR¹¹; R¹¹ isC1-C6 alkyl; or R^(1a) and R^(1c) are covalently bonded and, togetherwith more intermediate carbons, comprise —CH₂CH2 ₂—, or —CH═CH—. In astill further aspect, each of R^(1a), R^(1b), R^(1c), and R^(1d) isindependently hydrogen, C1-C6 alkyl, aryl, or —(CH₂)₂(C═O)OR¹¹; R¹¹ isC1-C6 alkyl; or R^(1a) and R^(1c) are covalently bonded and, togetherwith more intermediate carbons, comprise —CH₂CH₂—, or —CH═CH—.

In a further aspect, R^(1b) and and R^(1d) are each independentlyhydrogen, C1-C6 alkyl, aryl, or —(CH₂)_(m)(C═O)OR^(11;) R¹¹ is C1-C6alkyl; m is an integer selected from 0, 1, 2, and 3; and R^(1a) andR^(1c) are covalently bonded and, together with more intermediatecarbons, comprise —CH₂CH₂—, or —CH═CH—. In a still further aspect,R^(1b) and and R^(1d) are each hydrogen; and R^(1a) and R^(1c) arecovalently bonded and, together with more intermediate carbons, comprise—CH₂CH₂—, or —CH═CH—. In a yet further aspect, R^(1b) and and R^(1d) areeach hydrogen; and R^(1a) and R^(1c) are covalently bonded and, togetherwith more intermediate carbons, comprise —CH₂CH₂—. In an even furtheraspect, R^(1b) and and R^(1d) are each hydrogen; and R^(1a) and R^(1c)are covalently bonded and, together with more intermediate carbons,comprise —CH═CH—.

In a further aspect, each of R^(1a), R^(1b), R^(1c), and R^(1d) isindependently hydrogen, C1-C6 alkyl, aryl, or —(CH₂)_(m)(C═O)OR¹¹; R¹¹is C1-C6 alkyl; and m is an integer selected from 0, 1, 2, and 3.

In a further aspect, each of R^(1a), R^(1b), R^(1c), and R^(1d) isindependently hydrogen, methyl, ethyl, propyl, isopropyl, tert-butyl,sec-butyl, isobutyl, neopentyl, isopentyl, sec-pentyl, tert -pentyl,—(CH₂)(C═O)OCH₃, —(CH₂)(C═O)OCH₂CH₃, —(CH₂)(C═O)O(CH₂)₂CH₃,—(CH₂)(C═O)OCH(CH₃)₂, —(CH₂)(C═O)O(CH₂)₃CH₃, —(C═O)OCH₃, —(C═O)OCH₂CH₃,—(C═O)O(CH₂)₂CH₃, —(C═O)OCH(CH₃)₂, or —(C═O)O(CH₂)₃CH₃. In a stillfurther aspect, each of R^(1a), R^(1b), R^(1c), and R^(1d) isindependently hydrogen, methyl, ethyl, propyl, isopropyl, tert-butyl,sec-butyl, isobutyl, —(CH₂)(C═O)OCH₃, —(CH₂)(C═O)OCH₂CH₃,—(CH₂)(C═O)O(CH₂)₂CH₃, —(CH₂)(C═O)OCH(CH₃)₂, —(CH₂)(C═O)O(CH₂)₃CH₃,—(C═O)OCH₃, —(C═O)OCH₂CH₃, —(C═O)O(CH₂)₂CH₃, —(C═O)OCH(CH₃)₂, or—(C═O)O(CH₂)₃CH₃. In a yet further aspect, each of R^(1a), R^(1b),R^(1c), and R^(1d) is independently hydrogen, methyl, ethyl, propyl,isopropyl, —(CH₂)(C═O)OCH₃, —(CH₂)(C═O)0CH2CH3, —(CH₂)(C═O)O(CH₂)₂CH₃,—(CH₂)(C═O)OCH(CH₃)₂, —(C═O)OCH₃, —(C═O)OCH₂CH₃, —(C═O)O(CH₂)₂CH₃, or—(C═O)OCH(CH₃)₂. In an even further aspect, each of R^(1a), R^(1b),R^(1c), and R^(1d) is independently hydrogen, methyl, ethyl,—(CH₂)(C═O)OCH₃, —(CH₂)(C═O)OCH₂CH₃, —(C═O)OCH₃, or —(C═O)OCH₂CH₃. In astill further aspect, each of R^(1a), R^(1b), R^(1c), and R^(1d) isindependently hydrogen, methyl, —(CH₂)(C═O)OCH₃, or —(C═O)OCH₃.

In a further aspect, each of R^(1a), R^(1b), R^(1c), and R^(1d) isindependently hydrogen, —(CH₂)(C═O)OCH₃, —(CH₂)(C═O)OCH₂CH₃,—(CH₂)(C═O)O(CH₂)₂CH₃, —(CH₂)(C═O)OCH(CH₃)₂, —(CH₂)(C═O)O(CH₂)₃CH₃,—(C═O)OCH₃, —(C═O)OCH₂CH₃, —(C═O)O(CH₂)₂CH₃, —(C═O)OCH(CH₃)₂, or—(C═O)O(CH₂)₃CH₃. In a still further aspect, each of R^(1a), R^(1b),R^(1c), and R^(1d) is independently hydrogen, —(CH₂)(C═O)OCH₃,—(CH₂)(C═O)OCH₂CH₃, —(CH₂)(C═O)O(CH₂)₂CH₃, —(CH₂)(C═O)OCH(CH₃)₂,—(CH₂)(C═O)O(CH₂)₃CH₃, —(C═O)OCH₃, —(C═O)OCH₂CH₃, —(C═O)O(CH₂)₂CH₃,—(C═O)OCH(CH₃)₂, or —(C═O)O(CH₂)₃CH₃. In a yet further aspect, each ofR^(1a), R^(1b), R^(1c), and R^(1d) is independently hydrogen,—(CH₂)(C═O)OCH₃, —(CH₂)(C═O)OCH₂CH₃, —(CH₂)(C═O)O(CH₂)₂CH₃,—(CH₂)(C═O)OCH(CH₃)₂, —(C═O)OCH₃, —(C═O)OCH₂CH₃, —(C═O)O(CH₂)₂CH₃, or—(C═O)OCH(CH₃)₂. In an even further aspect, each of R^(1a), R^(1b),R^(1c), and R^(1d) is independently hydrogen, —(CH₂)(C═O)OCH₃,—(CH₂)(C═O)OCH₂CH₃, —(C═O)OCH₃, or —(C═O)OCH₂CH₃. In a still furtheraspect, each of R^(1a), R^(1b), R^(1c), and R^(1d) is independentlyhydrogen, —(CH₂)(C═O)OCH₃, or —(C═O)OCH₃.

In a further aspect, each of R^(1a), R^(1b), R^(1c), and R^(1d) isindependently hydrogen or C1-C6 alkyl. In a further aspect, each ofR^(1a), R^(1b), R^(1c), and R^(1d) is independently hydrogen, methyl,ethyl, propyl, isopropyl, tert-butyl, sec-butyl, isobutyl, neopentyl,isopentyl, sec-pentyl, or tert- pentyl. In a still further aspect, eachof R^(1a), R^(1b), R^(1c), and R^(1d) is independently hydrogen, methyl,ethyl, propyl, isopropyl, tert-butyl, sec-butyl, or isobutyl. In a yetfurther aspect, each of R^(1a), R^(1b), R^(1c), and R^(1d) isindependently hydrogen, methyl, ethyl, propyl, or isopropyl. In a yetfurther aspect, each of R^(1a), R^(1b), R^(1c), and R^(1d) isindependently methyl or ethyl. In a still further aspect, each ofR^(1a), R^(1b), R^(1c), and R^(1d) is independently hydrogen or methyl.In a yet further aspect, each of R^(1a), R^(1b), R^(1c), and R^(1d) ishydrogen. In an even further aspect, each of R^(1a), R^(1b), R^(1c), andR^(1d) is methyl.

In a further aspect, each of R^(1b) and R^(1d) is hydrogen, and each ofR^(1a) and R^(1c) is independently methyl, ethyl, propyl, isopropyl,tert-butyl, sec-butyl, isobutyl, neopentyl, isopentyl, sec-pentyl,tert-pentyl, —(CH₂)(C═O)OCH₃, —(CH₂)(C═O)OCH₂CH₃, —(CH₂)(C═O)O(CH₂)₂CH₃,—(CH₂)(C═O)OCH(CH₃)₂, —(CH₂)(C═O)O(CH₂)₃CH₃, —(C═O)OCH₃, —(C═O)OCH₂CH₃,—(C═O)O(CH₂)₂CH₃, —(C═O)OCH(CH₃)₂, or —(C═O)O(CH₂)₃CH₃. In a stillfurther aspect, each of R^(1b) and R^(1d) is hydrogen, and each ofR^(1a) and R^(1c) is independently hydrogen, methyl, ethyl, propyl,isopropyl, tert-butyl, sec-butyl, isobutyl, —(CH₂)(C═O)OCH₃,—(CH₂)(C═O)OCH₂CH₃, —(CH₂)(C═O)O(CH₂)₂CH₃, —(CH₂)(C═O)OCH(CH₃)₂,—(CH₂)(C═O)O(CH₂)₃CH₃, —(C═O)OCH₃, —(C═O)OCH₂CH₃, —(C═O)O(CH₂)₂CH₃,—(C═O)OCH(CH₃)₂, or —(C═O)O(CH₂)₃CH₃. In a yet further aspect, each ofR^(1b) and R^(1d) is hydrogen, and each of R^(1a) and R^(1c) isindependently hydrogen, methyl, ethyl, propyl, isopropyl,—(CH₂)(C═O)OCH₃, —(CH₂)(C═O)OCH₂CH₃, —(CH₂)(C═O)O(CH₂)₂CH₃,—(CH₂)(C═O)OCH(CH₃)₂, —(C═O)OCH₃, —(C═O)OCH₂CH₃, —(C═O)O(CH₂)₂CH₃, or—(C═O)OCH(CH₃)₂. In an even further aspect, each of R^(1b) and R^(1d) ishydrogen, and each of R^(1a) and R^(1c) is independently hydrogen,methyl, ethyl, —(CH₂)(C═O)OCH₃, —(CH₂)(C═O)OCH₂CH₃, —(C═O)OCH₃, or—(C═O)OCH₂CH₃. In a still further aspect, each of R^(1b) and R^(1d) ishydrogen, and each of R^(1a) and R^(1c) is independently hydrogen,methyl, —(CH₂)(C═O)OCH₃, or —(C═O)OCH₃.

In a further aspect, each of R^(1b) and R^(1d) is hydrogen, and each ofR^(1a) and R^(1c) is independently hydrogen, —(CH₂)(C═O)OCH₃,—(CH₂)(C═O)OCH₂CH₃, —(CH₂)(C═O)O(CH₂)₂CH₃, —(CH₂)(C═O)OCH(CH₃)₂,—(CH₂)(C═O)O(CH₂)₃CH₃, —(C═O)OCH₃, —(C═O)OCH₂CH₃, —(C═O)O(CH₂)₂CH₃,—(C═O)OCH(CH₃)₂, or —(C═O)O(CH₂)₃CH₃. In a still further aspect, each ofR^(1b) and R^(1d) is hydrogen, and each of R^(1a) and R^(1c) isindependently hydrogen, —(CH₂)(C═O)OCH₃, —(CH₂)(C═O)OCH₂CH₃,—(CH₂)(C═O)O(CH₂)₂CH₃, —(CH₂)(C═O)OCH(CH₃)₂, —(CH₂)(C═O)O(CH₂)₃CH₃,—(C═O)OCH₃, —(C═O)OCH₂CH₃, —(C═O)O(CH₂)₂CH₃, —(C═O)OCH(CH₃)₂, or—(C═O)O(CH₂)₃CH₃. In a yet further aspect, each of R^(1b) and R^(1d) ishydrogen, and each of R^(1a) and R^(1c) is independently hydrogen,—(CH₂)(C═O)OCH₃, —(CH₂)(C═O)OCH₂CH₃, —(CH₂)(C═O)O(CH₂)₂CH₃,—(CH₂)(C═O)OCH(CH₃)₂, —(C═O)OCH₃, —(C═O)OCH₂CH₃, —(C═O)O(CH₂)₂CH₃, or—(C═O)OCH(CH₃)₂. In an even further aspect, each of R^(1b) and R^(1d) ishydrogen, and each of R^(1a) and R^(1c) is independently hydrogen,—(CH₂)(C═O)OCH₃, —(CH₂)(C═O)OCH₂CH₃, —(C═O)OCH₃, or —(C═O)OCH₂CH₃. In astill further aspect, each of R^(1b) and R^(1d) is hydrogen, and each ofR^(1a) and R^(1c) is independently hydrogen, —(CH₂)(C═O)OCH₃, or—(C═O)OCH₃.

In a further aspect, each of R^(1b) and R^(1d) is hydrogen, and each ofR^(1a) and R^(1c) is independently hydrogen or C1-C6 alkyl. In a furtheraspect, each of R^(1b) and R^(1d) is hydrogen, and each of R^(1a) andR^(1c) is independently hydrogen, methyl, ethyl, propyl, isopropyl,tert-butyl, sec-butyl, isobutyl, neopentyl, isopentyl, sec-pentyl, ortert-pentyl. In a still further aspect, each of R^(1b) and R^(1d) ishydrogen, and each of R^(1a) and R^(1c) is independently hydrogen,methyl, ethyl, propyl, isopropyl, tert-butyl, sec-butyl, or isobutyl. Ina yet further aspect, each of R^(1b) and R^(1d) is hydrogen, and each ofR^(1a) and R^(1c) is independently hydrogen, methyl, ethyl, propyl, orisopropyl. In a yet further aspect, each of R^(1b) and R^(1d) ishydrogen, and each of R^(1a) and R^(1c)is independently methyl or ethyl.In a still further aspect, each of R^(1b) and R^(1d) is hydrogen, andeach of R^(1a) and R^(1c) is independently hydrogen or methyl. In a yetfurther aspect, each of R^(1b) and R^(1d) is hydrogen, and each ofR^(1a) and R^(1c) is methyl.

5. R² Group.

In one aspect, R² is hydrogen, C1-C6 alkyl, aryl, or—(CH₂)_(n)(C═O)OR¹²; R¹² is C1-C6 alkyl; and p is an integer selectedfrom 0, 1, 2, and 3. In a further aspect, R² is hydrogen, C1-C6 alkyl,aryl, or —(CH₂)_(n)(C═O)OR¹²; R¹² is C1-C6 alkyl; and p is an integerselected from 0, 1, and 2. In a still further aspect, R² is hydrogen,C1-C6 alkyl, aryl, or —(CH₂)_(n)(C═O)OR¹²; R¹² is C1-C6 alkyl; and p isan integer selected from 0 and 1. In a still further aspect, R² ishydrogen, C1-C6 alkyl, aryl, or —(CH₂)(C═O)OR¹²; and R¹² is C1-C6 alkyl.In an even further aspect, R² is hydrogen, C1-C6 alkyl, aryl, or—(CH₂)₂(C═O)OR¹²; and R¹² is C1-C6 alkyl.

In a further aspect, R² is hydrogen, methyl, ethyl, propyl, isopropyl,tert-butyl, sec -butyl, isobutyl, neopentyl, isopentyl, sec-pentyl,tert-pentyl, phenyl, —(CH₂)(C═O)OCH₃, —(CH₂)(C═O)OCH₂CH₃,—(CH₂)(C═O)O(CH₂)₂CH₃, —(CH₂)(C═O)OCH(CH₃)₂, —(CH₂)(C═O)O(CH₂)₃CH₃,—(C═O)OCH₃, —(C═O)OCH₂CH₃, —(C═O)O(CH₂)₂CH₃, —(C═O)OCH(CH₃)₂, or—(C═O)O(CH₂)₃CH₃. In a still further aspect, R² is hydrogen, methyl,ethyl, propyl, isopropyl, tert-butyl, sec-butyl, isobutyl, phenyl,—(CH₂)(C═O)OCH₃, —(CH₂)(C═O)OCH₂CH₃, —(CH₂)(C═O)O(CH₂)₂CH₃,—(CH₂)(C═O)OCH(CH₃)₂, —(CH₂)(C═O)O(CH₂)₃CH₃, —(C═O)OCH₃, —(C═O)OCH₂CH₃,—(C═O)O(CH₂)₂CH₃, —(C═O)OCH(CH₃)₂, or —(C═O)O(CH₂)₃CH₃. In a yet furtheraspect, R² is hydrogen, methyl, ethyl, propyl, isopropyl, phenyl,—(CH₂)(C═O)OCH₃, —(CH₂)(C═O)OCH₂CH₃, —(CH₂)(C═O)O(CH₂)₂CH₃,—(CH₂)(C═O)OCH(CH₃)₂, —(C═O)OCH₃, —(C═O)OCH₂CH₃, —(C═O)O(CH₂)₂CH₃, or—(C═O)OCH(CH₃)₂. In an even further aspect, R² is hydrogen, methyl,ethyl, phenyl, —(CH₂)(C═O)OCH₃, —(CH₂)(C═O)OCH₂CH₃, —(C═O)OCH₃, or—(C═O)OCH₂CH₃. In a still further aspect, R² is hydrogen, methyl,phenyl, —(CH₂)(C═O)OCH₃, or —(C═O)OCH₃.

In a further aspect, R² is hydrogen, —(CH₂)(C═O)OCH₃,—(CH₂)(C═O)OCH₂CH₃, —(CH₂)(C═O)O(CH₂)₂CH₃, —(CH₂)(C═O)OCH(CH₃)₂,—(CH₂)(C═O)O(CH₂)₃CH₃, —(C═O)OCH₃, —(C═O)OCH₂CH₃, —(C═O)O(CH₂)₂CH₃,—(C═O)OCH(CH₃)₂, or —(C═O)O(CH₂)₃CH₃. In a still further aspect, R² ishydrogen, —(CH₂)(C═O)OCH₃, —(CH₂)(C═O)OCH₂CH₃, —(CH₂)(C═O)O(CH₂)₂CH₃,—(CH₂)(C═O)OCH(CH₃)₂, —(CH₂)(C═O)O(CH₂)₃CH₃, —(C═O)OCH₃, —(C═O)OCH₂CH₃,—(C═O)O(CH₂)₂CH₃, —(C═O)OCH(CH₃)₂, or —(C═O)O(CH₂)₃CH₃. In a yet furtheraspect, R² is hydrogen, —(CH₂)(C═O)OCH₃, —(CH₂)(C═O)OCH₂CH₃,—(CH₂)(C═O)O(CH₂)₂CH₃, —(CH₂)(C═O)OCH(CH₃)₂, —(C═O)OCH₃, —(C═O)OCH₂CH₃,—(C═O)O(CH₂)₂CH₃, or —(C═O)OCH(CH₃)₂. In an even further aspect, R² ishydrogen, —(CH₂)(C═O)OCH₃, —(CH₂)(C═O)OCH₂CH₃, —(C═O)OCH₃, or—(C═O)OCH₂CH₃. In a still further aspect, R² is hydrogen,—(CH₂)(C═O)OCH₃, or —(C═O)OCH₃.

In a further aspect, R² is hydrogen or C1-C6 alkyl. In a further aspect,R² is hydrogen, phenyl, methyl, ethyl, propyl, isopropyl, tert-butyl,sec-butyl, isobutyl, neopentyl, isopentyl, sec-pentyl, or tert-pentyl.In a still further aspect, R² is hydrogen, phenyl, methyl, ethyl,propyl, isopropyl, tert-butyl, sec-butyl, or isobutyl. In a yet furtheraspect, R² is hydrogen, phenyl, methyl, ethyl, propyl, or isopropyl. Ina yet further aspect, R² is phenyl, methyl or ethyl. In a still furtheraspect, R² is hydrogen, phenyl, or methyl. In a yet further aspect, R²is hydrogen or phenyl. In an even further aspect, R² is methyl orphenyl.

In a further aspect, R² is hydrogen or C1-C6 alkyl. In a further aspect,R² is hydrogen, methyl, ethyl, propyl, isopropyl, tert-butyl, sec-butyl,isobutyl, neopentyl, isopentyl, sec-pentyl, or tert-pentyl. In a stillfurther aspect, R² is hydrogen, methyl, ethyl, propyl, isopropyl,tert-butyl, sec-butyl, or isobutyl. In a yet further aspect, R² ishydrogen, methyl, ethyl, propyl, or isopropyl. In a yet further aspect,R² is methyl or ethyl. In a still further aspect, R² is hydrogen ormethyl. In a yet further aspect, R² is hydrogen. In an even furtheraspect, R² is methyl.

6. R³ Group.

In one aspect, R³ is hydrogen, C1-C6 alkyl, aryl, trimethylsilyl, or—(CH₂),(C═O)OR¹⁵; R¹⁵ is C1-C6 alkyl; and r is an integer selected from0, 1, 2, and 3. In a further aspect, R³ is hydrogen, C1-C6 alkyl, aryl,trimethylsilyl, or —(CH₂),(C═O)OR¹⁵; R¹⁵ is C1-C6 alkyl; and r is aninteger selected from 0, 1, and 2. In a still further aspect, R³ ishydrogen, C1-C6 alkyl, aryl, trimethylsilyl, or —(CH₂),(C═O)OR¹⁵; R¹⁵ isC1-C6 alkyl; and r is an integer selected from 0 and 1. In a stillfurther aspect, R³ is hydrogen, C1-C6 alkyl, aryl, trimethylsilyl, or—(CH₂)(C═O)OR¹⁵; and R¹⁵ is C1-C6 alkyl. In an even further aspect, R³is hydrogen, C1-C6 alkyl, aryl, trimethylsilyl, or —(CH₂)₂(C═O)OR¹⁵; andR¹⁵ is C1-C6 alkyl.

In a further aspect, R³ is hydrogen, methyl, ethyl, propyl, isopropyl,tert-butyl, sec -butyl, isobutyl, neopentyl, isopentyl, sec-pentyl,tert-pentyl, phenyl, trimethylsilyl, —(CH₂)(C═O)OCH₃,—(CH₂)(C═O)OCH₂CH₃, —(CH₂)(C═O)O(CH₂)₂CH₃, —(CH₂)(C═O)OCH(CH₃)₂,—(CH₂)(C═O)O(CH₂)₃CH₃, —(C═O)OCH₃, —(C═O)OCH₂CH₃, —(C═O)O(CH₂)₂CH₃,—(C═O)OCH(CH₃)₂, or —(C═O)O(CH₂)₃CH₃. In a still further aspect, R³ ishydrogen, methyl, ethyl, propyl, isopropyl, tert-butyl, sec-butyl,isobutyl, phenyl, trimethylsilyl, —(CH₂)(C═O)OCH₃, —(CH₂)(C═O)OCH₂CH₃,—(CH₂)(C═O)O(CH₂)₂CH₃, —(CH₂)(C═O)OCH(CH₃)₂, —(CH₂)(C═O)O(CH₂)₃CH₃,—(C═O)OCH₃, —(C═O)OCH₂CH₃, —(C═O)O(CH₂)₂CH₃, —(C═O)OCH(CH₃)₂, or—(C═O)O(CH₂)₃CH₃. In a yet further aspect, R³ is hydrogen, methyl,ethyl, propyl, isopropyl, phenyl, trimethylsilyl, —(CH₂)(C═O)OCH₃,—(CH₂)(C═O)OCH₂CH₃, —(CH₂)(C═O)O(CH₂)₂CH₃, —(CH₂)(C═O)OCH(CH₃)₂,—(C═O)OCH₃, —(C═O)OCH₂CH₃, —(C═O)O(CH₂)₂CH₃, or —(C═O)OCH(CH₃)₂. In aneven further aspect, R³ is hydrogen, methyl, ethyl, phenyl,trimethylsilyl, —(CH₂)(C═O)OCH₃, —(CH₂)(C═O)OCH₂CH₃, —(C═O)OCH₃, or—(C═O)OCH₂CH₃. In a still further aspect, R³ is hydrogen, methyl,phenyl, trimethylsilyl, —(CH₂)(C═O)OCH₃, or —(C═O)OCH₃.

In a further aspect, R³ is hydrogen, methyl, ethyl, propyl, isopropyl,tert-butyl, sec -butyl, isobutyl, neopentyl, isopentyl, sec-pentyl,tert-pentyl, phenyl, —(CH₂)(C═O)OCH₃, —(CH₂)(C═O)OCH₂CH₃,—(CH₂)(C═O)O(CH₂)₂CH₃, —(CH₂)(C═O)OCH(CH₃)₂, —(CH₂)(C═O)O(CH₂)₃CH₃,—(C═O)OCH₃, —(C═O)OCH₂CH₃, —(C═O)O(CH₂)₂CH₃, —(C═O)OCH(CH₃)₂, or—(C═O)O(CH₂)₃CH₃. In a still further aspect, R³ is hydrogen, methyl,ethyl, propyl, isopropyl, tert-butyl, sec-butyl, isobutyl, phenyl,—(CH₂)(C═O)OCH₃, —(CH₂)(C═O)OCH₂CH₃, —(CH₂)(C═O)O(CH₂)₂CH₃,—(CH₂)(C═O)OCH(CH₃)₂, —(CH₂)(C═O)O(CH₂)₃CH₃, —(C═O)OCH₃, —(C═O)OCH₂CH₃,—(C═O)O(CH₂)₂CH₃, —(C═O)OCH(CH₃)₂, or —(C═O)O(CH₂)₃CH₃. In a yet furtheraspect, R³ is hydrogen, methyl, ethyl, propyl, isopropyl, phenyl,—(CH₂)(C═O)OCH₃, —(CH₂)(C═O)OCH₂CH₃, —(CH₂)(C═O)O(CH₂)₂CH₃,—(CH₂)(C═O)OCH(CH₃)₂, —(C═O)OCH₃, —(C═O)OCH₂CH₃, —(C═O)O(CH₂)₂CH₃, or—(C═O)OCH(CH₃)₂. In an even further aspect, R³ is hydrogen, methyl,ethyl, phenyl, —(CH₂)(C═O)OCH₃, —(CH₂)(C═O)OCH₂CH₃, —(C═O)OCH₃, or—(C═O)OCH₂CH₃. In a still further aspect, R³ is hydrogen, methyl,phenyl, —(CH₂)(C═O)OCH₃, or —(C═O)OCH₃.

In a further aspect, R³ is hydrogen, trimethylsilyl, —(CH₂)(C═O)OCH₃,—(CH₂)(C═O)OCH₂CH₃, —(CH₂)(C═O)O(CH₂)₂CH₃, —(CH₂)(C═O)OCH(CH₃)₂,—(CH₂)(C═O)O(CH₂)₃CH₃, —(C═O)OCH₃, —(C═O)OCH₂CH₃, —(C═O)O(CH₂)₂CH₃,—(C═O)OCH(CH₃)₂, or —(C═O)O(CH₂)₃CH₃. In a still further aspect, R³ ishydrogen, trimethylsilyl, —(CH₂)(C═O)OCH₃, —(CH₂)(C═O)OCH₂CH₃,—(CH₂)(C═O)O(CH₂)₂CH₃, —(CH₂)(C═O)OCH(CH₃)₂, —(CH₂)(C═O)O(CH₂)₃CH₃,—(C═O)OCH₃, —(C═O)OCH₂CH₃, —(C═O)O(CH₂)₂CH₃, —(C═O)OCH(CH₃)₂, or—(C═O)O(CH₂)₃CH₃. In a yet further aspect, R³ is hydrogen,trimethylsilyl, —(CH₂)(C═O)OCH₃, —(CH₂)(C═O)OCH₂CH₃,—(CH₂)(C═O)O(CH₂)₂CH₃, —(CH₂)(C═O)OCH(CH₃)₂, —(C═O)OCH₃, —(C═O)OCH₂CH₃,—(C═O)O(CH₂)₂CH₃, or —(C═O)OCH(CH₃)₂. In an even further aspect, R³ ishydrogen, trimethylsilyl, —(CH₂)(C═O)OCH₃, —(CH₂)(C═O)OCH₂CH₃,—(C═O)OCH₃, or —(C═O)OCH₂CH₃. In a still further aspect, R³ is hydrogen,—(CH₂)(C═O)OCH₃, or —(C═O)OCH₃.

In a further aspect, R³ is hydrogen, —(CH₂)(C═O)OCH₃,—(CH₂)(C═O)OCH₂CH₃, —(CH₂)(C═O)O(CH₂)₂CH₃, —(CH₂)(C═O)OCH(CH₃)₂,—(CH₂)(C═O)O(CH₂)₃CH₃, —(C═O)OCH₃, —(C═O)OCH₂CH₃, —(C═O)O(CH₂)₂CH₃,—(C═O)OCH(CH₃)₂, or —(C═O)O(CH₂)₃CH₃. In a still further aspect, R³ ishydrogen, —(CH₂)(C═O)OCH₃, —(CH₂)(C═O)OCH₂CH₃, —(CH₂)(C═O)O(CH₂)₂CH₃,—(CH₂)(C═O)OCH(CH₃)₂, —(CH₂)(C═O)O(CH₂)₃CH₃, —(C═O)OCH₃, —(C═O)OCH₂CH₃,—(C═O)O(CH₂)₂CH₃, —(C═O)OCH(CH₃)₂, or —(C═O)O(CH₂)₃CH₃. In a yet furtheraspect, R³ is hydrogen, —(CH₂)(C═O)OCH₃, —(CH₂)(C═O)OCH₂CH₃,—(CH₂)(C═O)O(CH₂)₂CH₃, —(CH₂)(C═O)OCH(CH₃)₂, —(C═O)OCH₃, —(C═O)OCH₂CH₃,—(C═O)O(CH₂)₂CH₃, or —(C═O)OCH(CH₃)₂. In an even further aspect, R³ ishydrogen, —(CH₂)(C═O)OCH₃, —(CH₂)(C═O)OCH₂CH₃, —(C═O)OCH₃, or—(C═O)OCH₂CH₃. In a still further aspect, R³ is hydrogen,—(CH₂)(C═O)OCH₃, or —(C═O)OCH₃.

In a further aspect, R³ is hydrogen, trimethylsilyl, or C1-C6 alkyl. Ina further aspect, R³ is hydrogen, trimethylsilyl, phenyl, methyl, ethyl,propyl, isopropyl, tert-butyl, sec-butyl, isobutyl, neopentyl,isopentyl, sec-pentyl, or tert-pentyl. In a still further aspect, R³ ishydrogen, trimethylsilyl, phenyl, methyl, ethyl, propyl, isopropyl,tert-butyl, sec-butyl, or isobutyl. In a yet further aspect, R³ ishydrogen, trimethylsilyl, phenyl, methyl, ethyl, propyl, or isopropyl.In a yet further aspect, R³ is phenyl, methyl or ethyl. In a stillfurther aspect, R³ is hydrogen, trimethylsilyl, phenyl, or methyl. Inayet further aspect, R³ is hydrogen, trimethylsilyl, or phenyl. In aneven further aspect, R³ is methyl, trimethylsilyl, or phenyl.

7. R¹⁰ Group.

In one aspect, R¹⁰ is C1-C6 alkyl. In a further aspect, R¹⁰ is methyl,ethyl, propyl, isopropyl, tert-butyl, sec-butyl, isobutyl, neopentyl,isopentyl, sec-pentyl, or tert-pentyl. In a still further aspect, R¹⁰ ismethyl, ethyl, propyl, isopropyl, tert-butyl, sec-butyl, or isobutyl. Ina yet further aspect, R¹⁰ is methyl, ethyl, propyl, or isopropyl. In ayet further aspect, R¹⁰ is methyl or ethyl. In a still further aspect,R¹⁰ is methyl.

8. R¹¹ Group.

In one aspect, R¹¹ is C1-C6 alkyl. In a further aspect, R¹¹ is methyl,ethyl, propyl, isopropyl, tert-butyl, sec-butyl, isobutyl, neopentyl,isopentyl, sec-pentyl, or tert-pentyl. In a still further aspect, R¹¹ ismethyl, ethyl, propyl, isopropyl, tert-butyl, sec-butyl, or isobutyl. Ina yet further aspect, R¹¹ is methyl, ethyl, propyl, or isopropyl. In ayet further aspect, R¹¹ is methyl or ethyl. In a still further aspect,R¹¹ is methyl.

9. R¹² Group.

In one aspect, R¹² is C1-C6 alkyl. In a further aspect, R¹² is methyl,ethyl, propyl, isopropyl, tert-butyl, sec-butyl, isobutyl, neopentyl,isopentyl, sec-pentyl, or tert-pentyl. In a still further aspect, R¹² ismethyl, ethyl, propyl, isopropyl, tert-butyl, sec-butyl, or isobutyl. Ina yet further aspect, R¹² is methyl, ethyl, propyl, or isopropyl. In ayet further aspect, R¹² is methyl or ethyl. In a still further aspect,R¹² is methyl.

10. R¹⁴ Group.

In one aspect, R¹⁴ is C1-C6 alkyl. In a further aspect, R¹⁴ is methyl,ethyl, propyl, isopropyl, tert-butyl, sec-butyl, isobutyl, neopentyl,isopentyl, sec-pentyl, or tert-pentyl. In a still further aspect, R¹⁴ ismethyl, ethyl, propyl, isopropyl, tert-butyl, sec-butyl, or isobutyl. Ina yet further aspect, R¹⁴ is methyl, ethyl, propyl, or isopropyl. In ayet further aspect, R¹⁴ is methyl or ethyl. In a still further aspect,R¹⁴ is methyl.

11. R¹⁵ Group.

In one aspect, R¹⁵ is C1-C6 alkyl. In a further aspect, R¹⁵ is methyl,ethyl, propyl, isopropyl, tert-butyl, sec-butyl, isobutyl, neopentyl,isopentyl, sec-pentyl, or tert-pentyl. In a still further aspect, R¹⁵ ismethyl, ethyl, propyl, isopropyl, tert-butyl, sec-butyl, or isobutyl. Ina yet further aspect, R¹⁵ is methyl, ethyl, propyl, or isopropyl. In ayet further aspect, R¹⁵ is methyl or ethyl. In a still further aspect,R¹⁵ is methyl.

12. R²⁰ Group.

In one aspect, R²⁰ is hydrogen, C1-C6 alkyl, or —(CH₂)_(p)(C═O)OR³⁰; R³⁰is C1-C6 alkyl; and p is an integer selected from 0, 1, 2, and 3. In afurther aspect, R²⁰ is hydrogen, C1-C6 alkyl, or —(CH₂)_(p)(C═O)OR³⁰;R³⁰ is C1-C6 alkyl; and p is an integer selected from 0, 1, and 2. In astill further aspect, R²⁰ is hydrogen, C1-C6 alkyl, or—(CH₂)_(p)(C═O)OR³⁰; R³⁰ is C1-C6 alkyl; and p is an integer selectedfrom 0 and 1. In a still further aspect, R²⁰ is hydrogen, C1-C6 alkyl,or —(CH₂)(C═O)OR³⁰; and R³⁰ is C1-C6 alkyl. In an even further aspect,R²⁰ is hydrogen, C1-C6 alkyl, or —(CH₂)₂(C═O)OR³⁰; and R³⁰ is C1-C6alkyl.

In a further aspect, R²⁰ is hydrogen, methyl, ethyl, propyl, isopropyl,tert-butyl, sec -butyl, isobutyl, neopentyl, isopentyl, sec-pentyl,tert-pentyl, —(CH₂)(C═O)OCH₃, —(CH₂)(C═O)OCH₂CH₃, —(CH₂)(C═O)O(CH₂)₂CH₃,—(CH₂)(C═O)OCH(CH₃)₂, —(CH₂)(C═O)O(CH₂)₃CH₃, —(C═O)OCH₃, —(C═O)OCH₂CH₃,—(C═O)O(CH₂)₂CH₃, —(C═O)OCH(CH₃)₂, or —(C═O)O(CH₂)₃CH₃. In a stillfurther aspect, R²⁰ is hydrogen, methyl, ethyl, propyl, isopropyl,tert-butyl, sec-butyl, isobutyl, —(CH₂)(C═O)OCH₃, —(CH₂)(C═O)OCH₂CH₃,—(CH₂)(C═O)O(CH₂)₂CH₃, —(CH₂)(C═O)OCH(CH₃)₂, —(CH₂)(C═O)O(CH₂)₃CH₃,—(C═O)OCH₃, —(C═O)OCH₂CH₃, —(C═O)O(CH₂)₂CH₃, —(C═O)OCH(CH₃)₂, or—(C═O)O(CH₂)₃CH₃. In a yet further aspect, R²⁰ is hydrogen, methyl,ethyl, propyl, isopropyl, —(CH₂)(C═O)OCH₃, —(CH₂)(C═O)OCH₂CH₃,—(CH₂)(C═O)O(CH₂)₂CH₃, —(CH₂)(C═O)OCH(CH₃)₂, —(C═O)OCH₃, —(C═O)OCH₂CH₃,—(C═O)O(CH₂)₂CH₃, or —(C═O)OCH(CH₃)₂. In an even further aspect, R²⁰ ishydrogen, methyl, ethyl, —(CH₂)(C═O)OCH₃, —(CH₂)(C═O)OCH₂CH₃,—(C═O)OCH₃, or —(C═O)OCH₂CH₃. In a still further aspect, R²⁰ ishydrogen, methyl, —(CH₂)(C═O)OCH₃, or —(C═O)OCH₃.

In a further aspect, R²⁰ is hydrogen, —(CH₂)(C═O)OCH₃,—(CH₂)(C═O)OCH₂CH₃, —(CH₂)(C═O)O(CH₂)₂CH₃, —(CH₂)(C═O)OCH(CH₃)₂,—(CH₂)(C═O)O(CH₂)₃CH₃, —(C═O)OCH₃, —(C═O)OCH₂CH₃, —(C═O)O(CH₂)₂CH₃,—(C═O)OCH(CH₃)₂, or —(C═O)O(CH₂)₃CH₃. In a still further aspect, R²⁰ ishydrogen, —(CH₂)(C═O)OCH₃, —(CH₂)(C═O)OCH₂CH₃, —(CH₂)(C═O)O(CH₂)₂CH₃,—(CH₂)(C═O)OCH(CH₃)₂, —(CH₂)(C═O)O(CH₂)₃CH₃, —(C═O)OCH₃, —(C═O)OCH₂CH₃,—(C═O)O(CH₂)₂CH₃, —(C═O)OCH(CH₃)₂, or —(C═O)O(CH₂)₃CH₃. In a yet furtheraspect, R²⁰ is hydrogen, —(CH₂)(C═O)OCH₃, —(CH₂)(C═O)OCH₂CH₃,—(CH₂)(C═O)O(CH₂)₂CH₃, —(CH₂)(C═O)OCH(CH₃)₂, —(C═O)OCH₃, —(C═O)OCH₂CH₃,—(C═O)O(CH₂)₂CH₃, or —(C═O)OCH(CH₃)₂. In an even further aspect, R²⁰ ishydrogen, —(CH₂)(C═O)OCH₃, —(CH₂)(C═O)OCH₂CH₃, —(C═O)OCH₃, or—(C═O)OCH₂CH₃. In a still further aspect, R²⁰ is hydrogen,—(CH₂)(C═O)OCH₃, or —(C═O)OCH₃.

In a further aspect, R²⁰ is hydrogen or C1-C6 alkyl. In a furtheraspect, R²⁰ is hydrogen, methyl, ethyl, propyl, isopropyl, tert-butyl,sec-butyl, isobutyl, neopentyl, isopentyl, sec-pentyl, or tert-pentyl.In a still further aspect, R²⁰ is hydrogen, methyl, ethyl, propyl,isopropyl, tert -butyl, sec-butyl, or isobutyl. In a yet further aspect,R²⁰ is hydrogen, methyl, ethyl, propyl, or isopropyl. In a yet furtheraspect, R²⁰ is methyl or ethyl. In a still further aspect, R²⁰ ishydrogen or methyl. In a yet further aspect, R²⁰ is hydrogen. In an evenfurther aspect, R²⁰ is methyl.

13. R²¹ Group.

In one aspect, R²¹ is hydrogen, C1-C6 alkyl, or —(CH₂)q(C═O)OR³¹; R³¹ isC1-C6 alkyl; and q is an integer selected from 0, 1, 2, and 3. In afurther aspect, R²¹ is hydrogen, C1-C6 alkyl, or —(CH₂)_(q)(C═O)OR³¹;R³¹ is C1-C6 alkyl; and q is an integer selected from 0, 1, and 2. In astill further aspect, R²¹ is hydrogen, C1-C6 alkyl, or—(CH₂)_(q)(C═O)OR³¹; R³¹ is C1-C6 alkyl; and q is an integer selectedfrom 0 and 1. In a still further aspect, R²¹ is hydrogen, C1-C6 alkyl,or —(CH₂)(C═O)OR³¹; and R³¹ is C1-C6 alkyl. In an even further aspect,R²¹ is hydrogen, C1-C6 alkyl, or —(CH₂)₂(C═O)OR³¹; and R³¹ is C1-C6alkyl.

In a further aspect, R²¹ is hydrogen, methyl, ethyl, propyl, isopropyl,tert-butyl, sec -butyl, isobutyl, neopentyl, isopentyl, sec-pentyl,tert-pentyl, —(CH₂)(C═O)OCH₃, —(CH₂)(C═O)OCH₂CH₃, —(CH₂)(C═O)O(CH₂)₂CH₃,—(CH₂)(C═O)OCH(CH₃)₂, —(CH₂)(C═O)O(CH₂)₃CH₃, —(C═O)OCH₃, —(C═O)OCH₂CH₃,—(C═O)O(CH₂)₂CH₃, —(C═O)OCH(CH₃)₂, or —(C═O)O(CH₂)₃CH₃. In a stillfurther aspect, R²¹ is hydrogen, methyl, ethyl, propyl, isopropyl,tert-butyl, sec-butyl, isobutyl, —(CH₂)(C═O)OCH₃, —(CH₂)(C═O)OCH₂CH₃,—(CH₂)(C═O)O(CH₂)₂CH₃, —(CH₂)(C═O)OCH(CH₃)₂, —(CH₂)(C═O)O(CH₂)₃CH₃,—(C═O)OCH₃, —(C═O)OCH₂CH₃, —(C═O)O(CH₂)₂CH₃, —(C═O)OCH(CH₃)₂, or—(C═O)O(CH₂)₃CH₃. In a yet further aspect, R²¹ is hydrogen, methyl,ethyl, propyl, isopropyl, —(CH₂)(C═O)OCH₃, —(CH₂)(C═O)OCH₂CH₃,—(CH₂)(C═O)O(CH₂)₂CH₃, —(CH₂)(C═O)OCH(CH₃)₂, —(C═O)OCH₃, —(C═O)OCH₂CH₃,—(C═O)O(CH₂)₂CH₃, or —(C═O)OCH(CH₃)₂. In an even further aspect, R²¹ ishydrogen, methyl, ethyl, —(CH₂)(C═O)OCH₃, —(CH₂)(C═O)OCH₂CH₃,—(C═O)OCH₃, or —(C═O)OCH₂CH₃. In a still further aspect, R²¹ ishydrogen, methyl, —(CH₂)(C═O)OCH₃, or —(C═O)OCH₃.

In a further aspect, R²¹ is hydrogen, —(CH₂)(C═O)OCH₃,—(CH₂)(C═O)OCH₂CH₃, —(CH₂)(C═O)O(CH₂)₂CH₃, —(CH₂)(C═O)OCH(CH₃)₂,—(CH₂)(C═O)O(CH₂)₃CH₃, —(C═O)OCH₃, —(C═O)OCH₂CH₃, —(C═O)O(CH₂)₂CH₃,—(C═O)OCH(CH₃)₂, or —(C═O)O(CH₂)₃CH₃. In a still further aspect, R²¹ ishydrogen, —(CH₂)(C═O)OCH₃, —(CH₂)(C═O)OCH₂CH₃, —(CH₂)(C═O)O(CH₂)₂CH₃,—(CH₂)(C═O)OCH(CH₃)₂, —(CH₂)(C═O)O(CH₂)₃CH₃, —(C═O)OCH₃, —(C═O)OCH₂CH₃,—(C═O)O(CH₂)₂CH₃, —(C═O)OCH(CH₃)₂, or —(C═O)O(CH₂)₃CH₃. In a yet furtheraspect, R²¹ is hydrogen, —(CH₂)(C═O)OCH₃, —(CH₂)(C═O)OCH₂CH₃,—(CH₂)(C═O)O(CH₂)₂CH₃, —(CH₂)(C═O)OCH(CH₃)₂, —(C═O)OCH₃, —(C═O)OCH₂CH₃,—(C═O)O(CH₂)₂CH₃, or —(C═O)OCH(CH₃)₂. In an even further aspect, R²¹ ishydrogen, —(CH₂)(C═O)OCH₃, —(CH₂)(C═O)OCH₂CH₃, —(C═O)OCH₃, or—(C═O)OCH₂CH₃. In a still further aspect, R²¹ is hydrogen,—(CH₂)(C═O)OCH₃, or —(C═O)OCH₃.

In a further aspect, R²¹ is hydrogen or C1-C6 alkyl. In a furtheraspect, R²¹ is hydrogen, methyl, ethyl, propyl, isopropyl, tert-butyl,sec-butyl, isobutyl, neopentyl, isopentyl, sec-pentyl, or tert-pentyl.In a still further aspect, R²¹ is hydrogen, methyl, ethyl, propyl,isopropyl, tert -butyl, sec-butyl, or isobutyl. In a yet further aspect,R²¹ is hydrogen, methyl, ethyl, propyl, or isopropyl. In a yet furtheraspect, R²¹ is methyl or ethyl. In a still further aspect, R²¹ ishydrogen or methyl. In a yet further aspect, R²¹ is hydrogen. In an evenfurther aspect, R²¹ is methyl.

14. R²² Group.

In one aspect, R²² is C1-C6 alkyl or —(C═O)OR³²; and R³² is C1-C6 alkyl.

In a further aspect, R²² is methyl, ethyl, propyl, isopropyl,tert-butyl, sec-butyl, isobutyl, neopentyl, isopentyl, sec-pentyl,tert-pentyl, —(C═O)OCH₃, —(C═O)OCH₂CH₃, —(C═O)O(CH₂)₂CH₃,—(C═O)OCH(CH₃)₂, or —(C═O)O(CH₂)₃CH₃. In a still further aspect, R²² ismethyl, ethyl, propyl, isopropyl, tert-butyl, sec-butyl, isobutyl,—(C═O)OC H₃, —(C═O)OCH₂CH₃, —(C═O)O(CH₂)₂CH₃, —(C═O)OCH(CH₃)₂, or—(C═O)O(CH₂)₃CH₃. In a yet further aspect, R²² is methyl, ethyl, propyl,isopropyl, —(C═O)OCH₃, —(C═O)OCH₂CH₃, —(C═O)O(CH₂)₂CH₃, or—(C═O)OCH(CH₃)₂. In an even further aspect, R²² is methyl, ethyl,—(C═O)OCH₃, or —(C═O)OCH₂CH₃. In a still further aspect, R²² is methylor —(C═O)OCH₃.

In a further aspect, R²² is —(C═O)OCH₃, —(C═O)OCH₂CH₃, —(C═O)O(CH₂)₂CH₃,—(C═O)OCH(CH₃)₂, or —(C═O)O(CH₂)₃CH₃. In a still further aspect, R²² is—(C═O)OCH₃, —(C═O)OCH₂CH₃, —(C═O)O(CH₂)₂CH₃, —(C═O)OCH(CH₃)₂, or—(C═O)O(CH₂)₃CH₃. In a yet further aspect, R²² is —(C═O)OCH₃,—(C═O)OCH₂CH₃, —(C═O)O(CH₂)₂CH₃, or —(C═O)OCH(CH₃)₂. In an even furtheraspect, R²² is —(C═O)OCH₃, or —(C═O)OCH₂CH₃. In a still further aspect,R²² is or —(C═O)OCH₃.

In a further aspect, R²² is C1-C6 alkyl. In a further aspect, R²² ismethyl, ethyl, propyl, isopropyl, tert-butyl, sec-butyl, isobutyl,neopentyl, isopentyl, sec-pentyl, or tert-pentyl. In a still furtheraspect, R²² is methyl, ethyl, propyl, isopropyl, tert-butyl, sec-butyl,or isobutyl. In a yet further aspect, R²² is methyl, ethyl, propyl, orisopropyl. In a yet further aspect, R²² is methyl or ethyl. In a stillfurther aspect, R²² is hydrogen or methyl. In a yet further aspect, R²²is hydrogen. In an even further aspect, R²² is methyl.

15. R³⁰ Group.

In one aspect, R³⁰ is C1-C6 alkyl. In a further aspect, R³⁰ is methyl,ethyl, propyl, isopropyl, tert-butyl, sec-butyl, isobutyl, neopentyl,isopentyl, sec-pentyl, or tert-pentyl. In a still further aspect, R³⁰ ismethyl, ethyl, propyl, isopropyl, tert-butyl, sec-butyl, or isobutyl. Ina yet further aspect, R³⁰ is methyl, ethyl, propyl, or isopropyl. In ayet further aspect, R³⁰ is methyl or ethyl. In a still further aspect,R³⁰ is methyl.

16. R³¹ Group.

In one aspect, R³¹ is C1-C6 alkyl. In a further aspect, R³¹ is methyl,ethyl, propyl, isopropyl, tert-butyl, sec-butyl, isobutyl, neopentyl,isopentyl, sec-pentyl, or tert-pentyl. In a still further aspect, R³¹ ismethyl, ethyl, propyl, isopropyl, tert-butyl, sec-butyl, or isobutyl. Ina yet further aspect, R³¹ is methyl, ethyl, propyl, or isopropyl. In ayet further aspect, R³¹ is methyl or ethyl. In a still further aspect,R³¹ is methyl.

17. R³² Group.

In one aspect, R³² is C1-C6 alkyl. In a further aspect, R³² is methyl,ethyl, propyl, isopropyl, tert-butyl, sec-butyl, isobutyl, neopentyl,isopentyl, sec-pentyl, or tert-pentyl. In a still further aspect, R³² ismethyl, ethyl, propyl, isopropyl, tert-butyl, sec-butyl, or isobutyl. Ina yet further aspect, R³² is methyl, ethyl, propyl, or isopropyl. In ayet further aspect, R³² is methyl or ethyl. In a still further aspect,R³² is methyl.

18. Example Structures.

In one aspect, an allenyne precursor compound can be present as:

or a subgroup thereof.

In one aspect, a terpenoid scaffold compound can be present as:

or a subgroup thereof.

C. Methods of Making the Disclosed Compounds

In one aspect, the present disclosure relates to methods of makingcompounds useful in the preparation of intermediates for synthesis ofterpenoid scaffolds, which can be useful in the development oftherapeutic compounds utilizing such chemical backbones. In one aspect,the disclosure relates to the disclosed synthetic manipulations. In afurther aspect, the disclosed compounds comprise the products of thesynthetic methods described herein. In a further aspect, the disclosedcompounds comprise a compound produced by a synthetic method describedherein. In a still further aspect, the disclosure comprises apharmaceutical composition comprising a therapeutically effective amountof the product of the disclosed methods and a pharmaceuticallyacceptable carrier. In a still further aspect, the disclosure comprisesa method for manufacturing a medicament comprising combining at leastone compound of any of disclosed compounds or at least one product ofthe disclosed methods with a pharmaceutically acceptable carrier ordiluent.

The compounds of this disclosure can be prepared by employing reactionsas shown in the disclosed schemes, in addition to other standardmanipulations that are known in the literature, exemplified in theexperimental sections or clear to one skilled in the art. The followingexamples are provided so that the disclosure might be more fullyunderstood, are illustrative only, and should not be construed aslimiting. For clarity, examples having a fewer substituent can be shownwhere multiple substituents are allowed under the definitions disclosedherein.

It is contemplated that each disclosed method can further compriseadditional steps, manipulations, and/or components. It is alsocontemplated that any one or more step, manipulation, and/or componentcan be optionally omitted from the disclosure. It is understood that adisclosed method can be used to provide the disclosed compounds. It isalso understood that the products of the disclosed methods can beemployed in the disclosed compositions, kits, and uses.

In one aspect, the terpenoid scaffolds of the present disclosure can beprepared generically by the synthetic scheme as shown below. Compoundsare represented in generic form, with substituents as noted in compounddescriptions elsewhere herein.

A more specific example of the procedure for the Knoevenagelcondensation reaction step is set forth below.

A suitable Knoevenagel adduct, such as compound 1 a, can be prepared byreaction shown above. Briefly, a suitable ketone, a suitablemalononitrile derivative (about 1 to about 2 equivalents), ammoniumacetate (about 0.1 to about 1 equivalents), and acetic acid (1equivalent) as shown above. The foregoing reactants are dissolved in asuitable solvent, e.g., benzene, (about 0.1 M to about 2.0 M withrespect to the ketone) and refluxed at a suitable temperature, e.g.,about 100° C. to about 200° C., in a suitable apparatus, e.g., using aDean -Stark apparatus. When the ketone is fully consumed (monitored byTLC, 4-16 hours), the reaction mixture is cooled to room temperature andsolvent is evaporated. The crude product can be further isolated bymethods known to one skilled in the art, e.g., filtration andconcentration, such as filteration through a silica plug and thenconcentrated under vacuum. The pure product, e.g., such as 1 a in theabove reaction scheme, can be further purified using methods known toone skilled in the art, e.g., column chromatography.

A more specific example of the procedure for the decojugativeα-alkylation reaction step is set forth below.

A suitable 1,5-enyne, such as compound 3 a, can be prepared using asuitable Knoevenagel adduct, such as 1 a, prepared by the precedingmethod. Briefly, the Knoevenagel adduct and a suitable propargylderivative (about 1 equivalent to about 3 equivalents), such as 2 a, aredissolved in suitable solvent, e.g. anhydrous DMF, (about 0.1 M to about1.0 M with respect to the limiting reagent). Finely ground K₂CO₃ (about2 equivalents to about 4 equivalents) is then added to the solution andstirred at a suitiable temperature, e.g. about room temperature, untilthe limiting reagent is consumed (monitored by TLC; 30 min -2 hrs.). Thecrude product can be further isolated by methods known to one skilled inthe art, e.g., the solution can be diluted with a suitable solvent,e.g., EtOAc, and washed with a suitable solvent, e.g., water, about 3-7times. The organic layer can then be washed with brine and dried, e.g.,using Na₂SO₄, followed by removal of the solvent, e.g, under reducedpressure. The crude material further purified using methods known to oneskilled in the art, e.g., via column chromatography.

A more specific example of the procedure for the one-potCope/α-alkylation reaction step is set forth below.

A suitable allenyne precursor, such as compound 5 aa, can be preparedusing a suitable 1,5-enyne, such as 3 a, prepared using the precedingmethods. Briefly, the 1,5-enyne is dissolved in a suitable solvent,e.g., toluene, and an inert gas, e.g., N₂, is bubbled through thesolution for a suitable period of time, e.g., about 1-10 minutes. Thesolution is then heated, e.g., using a pre-heated pie-block or oil bathin a screw cap pressure flask for a suitable period of time and at asuitable temperature, e.g., about 100° C. to about 250° C. for about 0.5hours to about 8 hours. When the reaction is completed (e.g., asdetermined by monitoring reaction progress using TLC or another suitablemeans), the solution is cooled to a suitable temperature, e.g., aboutroom temperature, and the solvent removed, e.g., under reduced pressure.The percent conversion can be calculated using ¹H NMR, and this data canbe utilized to determine the stoichiometry for the propargylation step.The crude product from the Cope rearrangement can be re-dissolved in asuitable solvent, e.g., THF (about 0.1 M to about 1.0 M with respect toallene 4 a) and added to a suspension of a metal hydride, e.g., NaH(about 0.5 equivalent to about 2 equivalents) in a suitable solvent,e.g., THF, at a suitable temperature, e.g., about −5° C. to about 10° C.A suitable propargyl derivative, e.g., compound 2 a, is then immediatelyadded to the solution and the reaction was warmed to a suitabletemperature, e.g., about 20° C. to about 30° C. Upon completion of thereaction (e.g., as determined by monitoring reaction progress using TLCor another suitable means), a suitable neutralizing solution, e.g.,saturated solution of NH₄Cl, is added to quench the NaH. The crudematerial can be isolated by suitable means know to one skilled in theart, e.g., taken up in a suitable solvent, such as ethyl acetate, washedwith H₂O and brine, dried with Na₂SO₄, and concentrated under reducedpressure. The compound can be further purified by means know to oneskilled in the art, e.g., column chromatography. In general, thegamma-allenyl Knoevenagel adduct is not isolated during preparation, andused directly in the next reaction step shown above.

Alternatively, suitable allenyne precursors can be prepared fromsuitable 1,5-enynes using a procedure for one-pot Cope/alkylidenereduction/α-alkylation reaction, a more specific example of which is setforth below.

A suitable allenyne precursor, such as compound 7 ad, can be preparedusing a suitable 1,5-enyne, such as 3 a, prepared using the precedingmethods. Briefly, the 1,5-enyne is dissolved in a suitable solvent,e.g., toluene, and Hantzsch ester (about 1 to about 3 equivalents) areadded. The solution is heated to a suitable temperature for a suitableperiod of time, e.g., about 100° C. to about 200° C. for about 4 hoursto about 24 hours, using a suitable apparatus, e.g., a pre-heatedpie-block in a screw cap pressure flask. When the reaction is completed(e.g., as determined by monitoring reaction progress using TLC oranother suitable means), the solution is cooled to a suitabletemperature, e.g., about room temperature, and the solvent removed,e.g., under reduced pressure. The crude product from the Coperearrangement is re-dissolved in a suitable solvent, e.g., DMF (about0.1 M to about 1.0 M with respect to allene 4 a), and added to asuspension of a suitable base, e.g., K₂CO₃ (about 2 to about 4equivalents), in a suitable solvent, e.g., DMF. A suitable propargylderivative, e.g., compound 2 d, is immediately added to the solution andthe reaction was warmed to suitable temperature, e.g., about 20° C. toabout 30° C. Upon completion of the reaction (e.g., as determined bymonitoring reaction progress using TLC or another suitable means), crudematerial can be isolated by suitable means know to one skilled in theart, e.g., taken up in a suitable solvent, such as ethyl acetate, washedwith H₂O and brine, dried with Na₂SO₄, and concentrated under reducedpressure. The compound can be further purified by means know to oneskilled in the art, e.g., column chromatography.

A more specific example of the procedure for the Pauson-Khand reactionstep is set forth below.

A suitable terpenoid scaffold, such as compound 6 aa, can be preparedfrom a suitable allenyne precursor, such as compound 5 aa, using aPauson-Khand reaction. Briefly, a flame -dried Schlenk flask is chargedwith 5 mol% [Rh(CO)₂Cl]₂ and the flask evacuated, then refilled with COgas. The allenyne precursor in a suitable solvent, e.g., toluene (0.01 Mwith respect to 5 aa), are added to the flask and a full balloon of COgas is bubbled through the solution. The balloon is replaced with asecond full balloon of CO gas and the reaction heated at a suitabletemperature, e.g., about 70° C. to about 150° C. When the reaction iscompleted (e.g., as determined by monitoring reaction progress using TLCor another suitable means), the solution is cooled to a suitabletemperature, e.g., room temperature, and solvent can be removed, e.g.,reduced pressure. The compound can be further purified by means know toone skilled in the art, e.g., column chromatography.

Alternatively, a flame-dried Schlenk flask can be charged with asolution of the allenyne in a suitable solvent, e.g., p-xylenes (0.005 Mwith respect to the allenyne precursor) under nitrogen. A full balloonof CO is bubbled through the solution before being replaced with asecond balloon of CO. The [Rh(CO)₂Cl]₂ catalyst (10 mol%) is added tothe reaction under an atmosphere of CO gas. The reaction is heated at asuitable temperature, e.g., about 90° C. to about 200° C., using asuitable apparatus, e.g., a preheated oil bath. When the reaction iscompleted (e.g., as determined by monitoring reaction progress using TLCor another suitable means), the solution is cooled to a suitabletemperature, e.g., room temperature, and solvent can be removed, e.g.,reduced pressure. The compound can be further purified by means know toone skilled in the art, e.g., column chromatography.

Before proceeding to the Examples, it is to be understood that thisdisclosure is not limited to particular aspects described, and as suchmay, of course, vary. Other systems, methods, features, and advantagesof foam compositions and components thereof will be or become apparentto one with skill in the art upon examination of the following drawingsand detailed description. It is intended that all such additionalsystems, methods, features, and advantages be included within thisdescription, be within the scope of the present disclosure, and beprotected by the accompanying claims. It is also to be understood thatthe terminology used herein is for the purpose of describing particularaspects only, and is not intended to be limiting. The skilled artisanwill recognize many variants and adaptations of the aspects describedherein. These variants and adaptations are intended to be included inthe teachings of this disclosure and to be encompassed by the claimsherein.

D. Examples

The following examples are put forth so as to provide those of ordinaryskill in the art with a complete disclosure and description of how thecompounds, compositions, articles, devices and/or methods claimed hereinare made and evaluated, and are intended to be purely exemplary of thedisclosure and are not intended to limit the scope of what the inventorsregard as their disclosure. Efforts have been made to ensure accuracywith respect to numbers (e.g., amounts, temperature, etc.), but someerrors and deviations should be accounted for. Unless indicatedotherwise, parts are parts by weight, temperature is in ° C. or is atambient temperature, and pressure is at or near atmospheric.

1. Exemplary Disclosed Compounds.

Exemplary disclosed compounds, and the associated reaction schemes, areshown in FIGS. 3A-8B. In the figures, exemplary compounds are shown asproducts of various reactions using compound labels or identifiers. Thecorrelation of particular compound labels or identifiers with structure,and the reactants used to prepare same, are specified in Tables 1-8below. For example, FIG. 3A shows a generalized reaction scheme forreaction of compounds 3 a-3 f to yield compounds 4 a-4 f, which was notisolated, but used in reaction directly with compounds 2 a-2 f to givethe desired products 5 aa-5 fd shown in FIG. 3B. For example, FIG. 3Bshows a particular compound, 5 aa, which is indicated as having beenprepared from reactants 3 a and 2 a. Yields and particular notes aregiven for each compound shown. General reaction details for each figureis noted above in the Brief Description of the Figures. The otherfigures are to be understood as explained for the particular figures andexamples referenced above for FIGS. 3A and 3B. Further experimentaldetails are provided herein below.

TABLE 1 Knoevenagel Adducts. Compound Identifier Structure Reactants 1a

1b

1c

1d

1e

1f

1l

1m

TABLE 2 Propargyl Derivatives. Compound Identifier Structure Reactants2 

2a

Commercially available 2b

Commercially available 2c

2d

2e

Commercially available 2f

TABLE 3 1,5-Enynes. Compound Identifier Structure Reactants 3a

3b

3c

3d

3e

3f

3g

3h

3i

3j

3k

3l

3m

TABLE 4 Allenyne Precursor. Compound Identifier Structure Procedure*Reactants 5aa

A

5ab

A

5ac

A

5ad

A

5bd

A

5cd

A

5dd

A

5de

A

5ed

A

5fd

A

5hd

A

5id

A

5jd

A

5kd

A

7ad

B

7dd

B

7ld

B

7md

B

*Procedure A is carried out using the one-pot Cope/α-alkylation reactionusing NaH in second step as described herein below; Procedure B iscarried out using the one-pot Cope/alkylidene reduction/α-alkylationreaction using a Hantzsch ester in the first step and K₂CO₃ in thesecond step as described herein below.

TABLE 5 Allene/Tethered π Substrates. Compound Identifier StructureReactants 7a

7b

7c

7d

7e

7f

TABLE 6 Terpenoid Scaffolds. Compound Identifier Structure Reactants 6aa

6cd

6dd

6de

6ed

6hd

6jd

6kd

6md

TABLE 7 Intramolecular Diels-Alder Furan Reaction Product. CompoundIdentifier Structure Reactants 8

TABLE 8 Functional Group Interconversion Reaction Products. CompoundIdentifier Structure Reactants 9a

9b

9c

9d

In the discussion herein below, reference is made to different reactionschemes which are further detailed in the figures as follows: Scheme 1,see FIG. 2; Scheme 2, see FIGS. 3A -3B; Scheme 3, see FIGS. 4A-4C;Scheme 4, see FIGS. 5A-5C; Scheme 5, see FIGS. 6A -6B; Scheme 6, seeFIGS. 7A-7B; and Scheme 7, see FIGS. 8A-8B.

Scheme 1. The strategy for assembling 6/7/5 scaffolds. Inspired bysynthetically challenging 6/7/5 tricyclic terpenoid natural products(FIG. 1), which offer promising biological activities by way of uniquefunctionalization and oxidation patterns (e.g., see Ref. 7), thedisclosed methods were developed to provide novel approaches to tunablyassemble terpenoid cores or scaffolds decorated with numerous functionalgroups (Scheme 1, FIG. 2): Deconjugative α-alkylation (e.g., see Ref. 8)of Knoevenagel adduct 1 with propargyl bromide 2 prepares the 1,5-enyne3. Enyne [3,3] Cope rearrangement (e.g., see Ref. 9) results inγ-allenyl Knoevenagel adduct 4 and repeating the deconjugativeα-propargylation step affords the 1,7-allenyne 5. Finally,allenic-Pauson-Khand reaction (e.g., see Refs. 6f, 6k, 10, 11) completesthe 6/7/5 core structure with a variety of substitution, controlled bychoice of starting material (“R”-groups), and unique functional handles(e.g. gem-dinitrile, alkene, s-trans-diene, an enone) fordiversification.

The disclosed synthetic methods have several notable features. First,they employs only abundant starting materials(ketones+malononitrile=Knoevenagel adducts; propargyl electrophiles).Second, the coupling reactions (deconjugative α-alkylation) areoperationally simple due to the ease of Knoevenagel adduct aniongeneration (γ-C—H pK_(a)<10; e.g., see Ref. 12). The disclosed methodsalso provide approaches to a rare 1,5-enyne Cope rearrangement (e.g.,see Ref. 9). Although the reaction has been described (three isolatedexamples, e.g., see Ref. 9) and computationally examined (e.g., see Ref.13), it has had little to no application in synthesis. The disclosedmethods also surprisingly improve the scope and understanding of theCope rearrangement of 3,3-dicyano-1,5-enynes. The final feature of thedisclosed methods is the use of the allenic-Pauson-Khand reaction (PKR).When preparing hydroazulenes by PKR, it is essential that the “alkene”coupling partner be an allene (e.g., see Refs. 6f, 6k, 10, 11).

Scheme 2. Scope of 1,7-allenyne synthesis. 1,5-enynes. 3 a-3 f bearing aterminal alkyne were prepared by reaction of Knoevenagel adducts andpropargyl bromide in DMF with K₂CO₃ as a base. In general, 1,5-enynesyntheses are rapid and high yielding on both milligram and gram scales.Surprisingly, the reaction was successful, particularly in view ofuncertainties regarding the 1,5-enyne [3,3] Cope rearrangement due tothe minimal prior precedent (e.g., see Ref. 9). The disclosed methodssurprisingly provide a means to this reaction, e.g., the reaction wentforward at 150° C. in toluene in screw-cap pressure flasks (Scheme 2,FIGS. 3A-3B). It was determined that it was typically most practical tonot isolate the γ-allenyl Knoevenagel adducts 4. Rather, following [3,3]rearrangement, the solvent was “swapped” (toluene for THF) and theallene was directly treated with NaH and a second equivalent of a 1°propargyl bromide derivative to yield the 1,7-allenynes 5 in good yieldover the telescoped procedure (20-56% yield of 1,7-allenynes). Reportedin Scheme 2 are two -step yields, averaging 45%-75% yield per step,where inexpensive and abundant starting materials are converted intosynthetically useful 1,7-allenyes. Notably, the procedure is scalableand reproducible; the reaction sequence was examined on the 300 mg-2gram scale with little change in efficiency.

Through the sequence, cyclohexenyl substitution is controlled by choiceof cycloalkanone starting material. For example, substrates 3 c and 3 d,prepared from 4-substituted cyclohexanone, were found to yield theallenynes 5 cd and 5 dd. Furthermore, the Cope rearrangement wasdiastereoselective (>20:1 dr) in these cases. Alkyne substitution isvaried by choice of propargyl bromide starting material. For example,1,7-allenynes were prepared bearing a phenylacetylene moiety (5 ac), apropargyl acetate (5 ad), and a TMS -alkyne (5 de). Finally, bicyclic1,7-allenynes 5 ed and 5 fd were prepared from tropinone (3 e) and the(4+3) adduct (3 f) of cyclopentadiene and trichloroacetone.

Scheme 3. 1,5-enynes that do not (A) and do (B) undergo [3,3]rearrangement. 1,5-enynes that do not (FIG. 4A) and do (FIG. 4B) undergo[3,3] rearrangement. The [3,3] Cope rearrangement of 1,5-enynes 3 g-3 kbearing an internal alkyne (Scheme 3) was examined. Initial studiesrevealed a method limitation: cyclohexenyl substrates such as 3 gdegraded under thermal conditions. Specifically, conversion was onlyobserved at a higher temperature (200° C.) compared to the results inScheme 2 (150° C.), but no desired product could be isolated.Interestingly, the bridged bicyclic substrates 3 h-3 k underwent anefficient Cope rearrangement and the desired allenynes could be isolatedin good yields over the telescoped sequence.

Allenes are generally useful for intramolecular cycloisomerization(e.g., see Ref. 15). As such, other functionalized electrophiles wereexamined in order to prepare diverse allene/tethered-π substrates(Scheme 4). Enyne Cope rearrangement/allylation with cinnamyl bromideresulted in separable products 7 a and 7 b in 60% and 23% yields,respectively. Enyne Cope rearrangement/Pd-catalyzed allylation withcinnamyl acetate intriguingly resulted in diastereo-, γ-, andbranch-selective allylation in good yield (product 7 c). At this point,we do not understand why this combination of substrates and catalystgives this result, although it is interesting and potentially useful formaking complex polycyclic small molecules. It should also be noted that7 a can convert to 7 c by thermal [3,3] rearrangement (e.g., see Ref.16). Considering these results, it was surprising to find that enyneCope rearrangement/Pd -catalyzed allylation with sorbyl acetate resultsexclusively in linear-selective deconjugative α-allylation. Reaction offuran-containing alkyl chloride was also examined. The enyne-Coperearrangement/alkylation resulted in a separable mixture ofdeconjugative α-alkylation product 7 e and γ-alkylated product 7 f.

Scheme 4. Other allene/tethered Tr-systems prepared. Using theallenic-Pauson -Khand reaction (e.g., see Refs. 6f, 6k, 10, 11), the1,7-allenynes were converted into their respective 6/7/5 tricycloalkanecores without incident by the standard literature protocol developed andapplied by Brummond and others (Scheme 5; e.g., see Refs. 6f, 6k, 10,11). The cores are highly complex and diverse, considering the sequenceis four steps from abundant starting materials.

Scheme 5. Synthesis of 6/7/5 tricycloalkane terpenoid scaffolds.Allenyne precursor compounds prepared by the methods discussed hereinwere converted in a single step reaction to 6/7/5 tricycloalkaneterpenoid scaffolds with a variety of substitution, controlled by choiceof starting material (choice of substituent groups in the variousreactants in the generalized reaction scheme), and unique functionalhandles (e.g. gem-dinitrile, alkene, s -trans-diene, an enone) fordiversification.

Scheme 6. An intramolecular Diels-Alder furan reaction. The reaction offuran- containing allene 7 e with regard to intramolecular Diels-Alderfuran (IMDAF) reactivity (Scheme 6; see FIG. 7A; e.g., see Ref. 17). Itwas surprising to find that thermal conditions could convert 7 e to thefunctionally dense polycycloalkane 8 in 39% yield. 8 contains a 6/6/7tricycloalkane framework, two-heteroatomic bridges, and numerous otherfunctional groups and was prepared in four steps from inexpensivecommercial materials. Notably, there are terpenoid natural products thatbear a related 6/6/7 tricycloalkane tricycloalkane ring system (FIG. 7B;and e.g., see Ref. 18).

Scheme 7. Functional group interconversion reactions. The most reactiveolefin toward epoxidation was the γ,δ-olefin on the conjugated dienonefor substrate 6 dd. For the more strained scaffold 6 kd, thebicyclo[3.2.1]octene was most reactive yielding 9 c. Also, the ketonecould be reduced using NaBH₄ to prepare 9 b. Finally, ring-opening/crossmetathesis could be performed on the bicyclo[3.2.1]octene core yielding9 d.

In conclusion, the disclosed methods provide a new route to 6/7/5tricycloalkane frameworks. The sequence hinged on the development ofpoorly understood 3,3-dicyano-1,5-enyne Cope rearrangement. Thedisclosed methods provide novel conditions for these reaction and takethis reaction into novel chemical space well beyond the currentlimitations for this transformation. The disclosed methods provide novelmethods for the synthesis of diverse linear 6/7/5 tricycloalkanes, aswell as a highly complex 6/6/7 tricycloalkane, all in four steps fromcycloalkanone, malononitrile, and two different alkyl electrophiles(propargyl-, allyl-, and furan-containing electrophiles).

2. General Experimental

All commercial materials were used without further purification. ¹H NMRand ¹³C NMR spectra were recorded in CDCl₃ (with CHCl₃ residual peak asan internal standard), DMSO -d6 (with DMSO-d5 residual peak as aninternal standard), or toluene-d₈ (with toluene-d₇ residual peak as aninternal standard) using a 500 MHz or 600 MHz spectrometer (see: (a)Gottlieb, H. E., et al. J. Org. Chem. 1997, 62, 7512; and (b) Fulmer, G.R., et al. Organometallics 2010, 29, 2176. Variable temperature NMR (80°C.) was used to record all samples run in DMSO-d₆ or toluene-d₈. All ¹³CNMR spectra were recorded with complete proton decoupling. HRMS datawere recorded on Agilent Time of Flight 6200 spectrometer. Reactionprogress was monitored by thin-layer chromatography (TLC) and visualizedby UV light, phosphomolybdic acid stain, and KMnO₄ stain. Commerciallyavailable anhydrous DMF stored over molecular sieves was used forα-alkylation of Knoevenagel adducts and commercially available anhydrousmethanol was used for NaBH₄ reduction. All other reactions (with theexception of Knoevenagel condensation reactions) were carried out usinganhydrous solvents obtained dried by passing through activated aluminacolumns. Bicyclo[3.2.1]oct-6-en-3-one was prepared according to apreviously published procedure (see Rudroff, F., et al. Tetrahedron2016, 72(46), 7212).

3. General Procedure For Knoevenagel Condensation

The ketone, malonate derivative (1.1 equivalents), ammonium acetate (0.5equivalents), and acetic acid (1 equivalent) were dissolved in benzene(1.0 M with respect to the ketone) and refluxed at 130° C. using aDean-Stark apparatus. When the ketone was fully consumed (monitored byTLC, 4-16 hrs.), the reaction mixture was cooled to room temperature andsolvent was evaporated. The crude product was then filtered through asilica plug and then concentrated under vacuum. The pure products wereisolated via column chromatography (hexane - ethyl acetate) unlessotherwise noted. Using the foregoing method, compounds 1 a-1 f and 1 l-1m were prepared, and are described in further detail herein below.

-   -   a. 2-CYCLOHEXYLIDENEMALONONITRILE (1A).

The compound was isolated as a colorless Oil, 95% yield, 7.07 g; andpurified using 10% EtOAc in hexane; R_(f)=0.3 (10% EtOAc in hex).Analytical data were consistent with that in the reference (Longstreet,A. R., et al., Org. Lett. 2013, 15 (20), 5298).

-   -   b. METHYL 2-CYANO-2-CYCLOHEXYLIDENEACETATE (1B).

The compound was isolated as a light yellow oil, 43% yield, 3.88 g; andpurified using gradient: 5%-15% EtOAc in hexane. ¹H NMR (500 MHz, CDCl₃)δ 3.73 (s, 3H), 2.94-2.86 (t, J=6.1 Hz, 2H), 2.58 (t, J=6.4 Hz, 2H),1.77-1.54 (m, 6H). ¹³C NMR (125 MHz, CDCl₃) δ 180.4, 162.2, 115.4,101.4, 52.3, 36.7, 31.4, 28.5, 28.1, 25.4. HRMS (ESI-TOF) m/z: [M+H]⁺Calcd for C₁₀H₁₄NO₂ 180.1019; Found 180.1016. R_(f)=0.56 (20% EtOAc inhexane).

-   -   c. 2-(4-METHYLCYCLOHEXYLIDENE)MALONONITRILE (1C).

The compound was isolated as an orange oil, 100% conversion, used crudein next step, 1H NMR (300 MHz, CDCl₃) δ 3.08-2.94 (m, 2H), 2.44-2.27 (m,2H), 2.08-1.96 (m, 2H), 1.75 (dddp, J=13.9, 10.3, 6.7, 3.3 Hz, 1H),1.32-1.16 (m, 2H), 0.98 (d, J=6.6 Hz, 3H). ¹³C NMR (125 MHz, CDCl₃) δ184.9, 111.8, 82.8, 35.7, 34.2, 31.4, 20.9. HRMS (ESI-TOF) m/z: [M−H]⁻Calcd for C₁₀H₁₁N₂159.0928; Found 159.0926. R_(f)=0.30 (10% EtOAc inhexane).

-   -   d. ETHYL 4-(DICYANOMETHYLENE)CYCLOHEXANE-1-CARBOXYLATE (1D).

100% conversion, used crude in next step. ¹H NMR (500 MHz, CDCl₃) δ 4.17(q, J=7.1 Hz, 2H), 2.95 (dt, J=14.8, 5.1 Hz, 2H), 2.68 (tt, J=8.9, 4.1Hz, 1H), 2.55 (ddd, J=14.8, 10.1, 4.9 Hz, 2H), 2.15 (dq, J=15.1, 5.4,5.0 Hz, 2H), 1.93 (dtd, J=14.0, 9.7, 4.5 Hz, 2H), 1.27 (t, J=7.2 Hz,3H). ¹³C NMR (125 MHz, CDCl₃) δ 182.5, 173.3, 111.5, 83.6, 61.0, 40.5,32.6, 29.1, 14.2. HRMS (ESI-TOF) m/z: [M−NH₄]⁺ Calcd for C₁₂H₁₈N₃O₂236.1394; Found 236.1405. R_(f)=0.23 (20% EtOAc in hexane)

-   -   e. TERT-BUTYL        3-(DICYANOMETHYLENE)-8-AZABICYCLO[3.2.1]0CTANE-8-CARBOXYLATE        (1E).

Tan solid, 100% conversion, used crude in next step. ¹H NMR (500 MHz,CDCl₃) δ 4.45 (bs, 2H), 2.92 (d, J=15.6 Hz, 2H), 2.72 (d, J=49.6 Hz,2H), 2.05 (bs, 2H), 1.55 (d, J=8.3 Hz, 2H), 1.48 (s, 9H). ¹³C NMR (125MHz, CDCl₃) δ 179.0, 153.1, 111.3, 87.9, 81.0, 77.4, 77.2, 76.9, 54.0,40.6, 40.0, 28.5. HRMS (ESI-TOF) m/z: [M+Na]⁺ Calcd for C₁₅H₁₉N₃O₂Na296.1369; Found 296.1365. R_(f)=0.28 (20% EtOAc in hexane)

-   -   f. 2-(BICYCLO[3.2.1]OCT-6-EN-3-YLIDENE)MALONONITRILE (1F).

White solid, 57% yield, 1.4 g. Purified using 10% EtOAc in hexane. ¹HNMR (500 MHz, Chloroform-d) δ 5.97 (s, 2H), 2.97 (dd, J=15.4, 2.4 Hz,2H), 2.91 (d, J=2.6 Hz, 2H), 2.57 (dd, J=18.4, 2.9 Hz, 2H), 2.08 (dtt,J=10.5, 5.2, 2.5 Hz, 1H), 1.68 (d, J=11.0 Hz, 1H). ¹³C NMR (125 MHz,cdc1 ₃) δ 183.4, 135.0, 111.6, 88.2, 42.5, 38.9, 37.2. HRMS (ESI-TOF)m/z: [M+Na]⁺ Calcd for C₁₁H₁₀N₂Na 193.0736; Found 193.0734. R_(f)=0.4(20% EtOAc in hexane).

-   -   g. N-(4-(DICYANOMETHYLENE)CYCLOHEXYL)ACETAMIDE (1L).

Orange solid, 97% yield, 6.3 g. Used without further purification. ¹HNMR (500 MHz, CD₃OD) δ 3.99 (tt, J=10.2, 4.1 Hz, 1H), 2.95 (dtd, J=14.7,4.8, 1.6 Hz, 2H), 2.68-2.51 (m, 2H), 2.20-2.07 (m, 2H), 1.94 (m, 4H),1.65-1.44 (m, 2H). ¹³C NMR (125 MHz, CD₃OD) δ 182.8, 171.3, 111.3, 82.5,46.0, 31.6, 31.5, 21.2. HRMS (ESI-TOF) m/z: [M−Na]⁺ Calcd forC₁₁H₁₃N₃ONa 226.0951; Found 226.0961.

-   -   h. 2-(1,4-DIOXASPIRO[4.5]DECAN-8-YLIDENE)MALONONITRILE (1M).

White solid, 80% yield, 5.2 g. Recrystallized in ethanol. R_(f)=0.42(30% EtOAc in hex). Analytical data is consistent with that previouslyreported (Lahtigui, O., et al., Angew. Chemie. Int. Ed. 2016, 55 (51),15792.).

4. Preparation of Propargyl Electrophiles (Compounds 2, 2C, 2D, and 2F).

-   -   a. 4-HYDROXYBUT-2-YN-1-YL ACETATE (2).

The diol (3 equivalents, 25.3 g, 293.86 mmol) and acetic anhydride (1equivalent, 10 g, 97.95 mmol, 9.26 mL) were dissolved in THF (1.0 M withrespect to the limiting reagent) and the solution was stirred at 40° C.for 18 hours. The solvent was then removed under reduced pressure andthe crude product was filtered over a silica plug using 1:1 EtOAc-hexane to remove most of the excess diol. The product was purifiedusing column chromatography (gradient: 20%→40% EtOAc in hexane). Paleyellow oil, 68% yield, 8.51 g. Analytical data is consistent with thatpreviously reported (Pacheco, M. C.; Gouverneur, V. Org. Lett. 2005,7(7), 1267).

-   -   b. (3-BROMOPROP-1-YN-1-YL)BENZENE (2C).

The propargyl alcohol (1.0 g, 7.57 mmol, 0.94 mL) was dissolved in 30 mLanhydrous ether and the solution was cooled to 0° C. PBr₃ (1.5equivalents, 3.07 g, 11.35 mmol, 1.07 mL) was then added dropwise, andthe solution was allowed to warm to room temperature. Upon completion ofthe reaction (monitored by TLC) the reaction mixture was added to iceand extracted with EtOAc. The organic layer was then washed with asaturated solution of NaHCO₃ and brine and dried over Na₂SO₄. The crudeproduct was concentrated under reduced pressure and purified via columnchromatography (15% EtOAc in hexane). Yellow oil, 61% yield, 900 mg.Analytical data is consistent with that previously reported (Vyas, D.;Hazra, C.; Oestreich, M. Org. Lett. 2011, 13 (16), 4462).

-   -   c. 4-BROMOBUT-2-YN-1-YL ACETATE (2D).

The propargyl alcohol (5 g, 39.02 mmol) was dissolved in 120 mLanhydrous DCM and CBr₄ (12.94 g, 39.02 mmol) was added to the solution.The reaction was then cooled to 0° C. and PPh₃ (10.24 g, 39.02 mmol) wasadded in small portions. After warming to room temperature, the reactionwas stirred for 4 hours before quenching with 25 mL MeOH. The solventswere evaporated and the crude product was filtered through a silica plug(1:1 hexane -ethyl acetate). The product was then concentrated underreduced pressure and purified via column chromatography (10% ethylacetate in hexane). Colorless oil, 73% yield, 5.46 g. Analytical data isconsistent with that in the reference (Fischer, M., et al., Eur. J. Org.Chem. 2011, 2011 (9), 1645).

-   -   d. (2E,4E)-HEXA-2,4-DIEN-1-YL ACETATE (2F).

Sorbyl alcohol (1 g, 10.19 mmol, 1.12 mL) and acetic anhydride (3.12 g,30.57 mmol, 2.89 mL) were heated to 60° C. neat for 5 hours. Uponcompletion of the reaction (monitored by TLC), the solution was taken upin ethyl acetate and washed with a saturated solution of NaHCO₃, thenbrine. The organic layer was dried over Na₂SO₄ and the solvent wasremoved under reduced pressure. Colorless oil, 99% yield, 1.42 g.

5. General Procedure for Decojugative α-Alkylation.

Knoevenagel adduct 1 and 2 equivalents of a propargyl bromide derivative2 were dissolved in anhydrous DMF (0.5 M with respect to the limitingreagent). Finely ground K₂CO₃ (3 equivalents) was then added to thesolution and stirred at room temperature until the limiting reagent wasconsumed (monitored by TLC; 30 min-2 hrs.). The solution was thendiluted with EtOAc and washed with H₂O five times. The organic layer wasthen washed with brine and dried with Na₂SO₄. The solvent was removedunder reduced pressure and the crude material purified via columnchromatography (hexane-ethyl acetate) unless otherwise noted. Using theforegoing method, compounds 3 a-3 f and 3 h-3 m were prepared, and aredescribed in further detail herein below.

-   -   a. 2-(CYCLOHEX-1-EN-1-YL)-2-(PROP-2-YN-1-YL)MALONONITRILE (3A).

Pale yellow oil, 93% yield, 2.34 g. Purified using 10% EtOAc in hexane.¹H NMR (500 MHz, CDCl₃) δ 6.30 (dq, J=3.8, 2.0 Hz, 1H), 2.97 (d, J=2.6Hz, 2H), 2.35 (t, J=2.5 Hz, 1H), 2.23-2.11 (m, 5H), 1.79-1.72 (m, 2H),1.63 (pd, J=6.9, 6.2, 4.1 Hz, 2H). ¹³C NMR (125 MHz, CDCl₃) δ 131.0,127.0, 113.9, 75.2, 74.9, 43.4, 28.8, 25.4, 24.5, 22.3, 21.3. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₁₂H₁₃N₂ 185.1073; Found 185.1080. [M+H]⁺Calcd for C₁₂H₁₂N₂Na 207.0893; Found 207.0883. R_(f)=0.51 (20% EtOAc inhexane)

-   -   b. METHYL 2-CYANO-2-(CYCLOHEX-1-EN-1-YL)PENT-4-YNOATE (3B).

Pale yellow oil, 73% yield, 900 mg. Purified using 10% EtOAc in hexane.¹H NMR (500 MHz, CDCl₃) δ 6.11 (tt, J=3.9, 1.5 Hz, 1H), 3.84 (s, 3H),2.98 (dd, J=16.7, 2.6 Hz, 1H), 2.83 (dd, J=16.8, 2.7 Hz, 1H), 2.21-2.07(m, 3H), 2.08-1.94 (m, 2H), 1.74-1.50 (m, 4H). ¹³C NMR (125 MHz, CDCl₃)δ 167.1, 129.8, 128.8, 117.6, 77.6, 72.8, 54.8, 54.1, 25.7, 25.5, 24.8,22.6, 21.5. HRMS: (ESI-TOF) m/z: [M+H]⁺ Calcd for C₁₃H₁₆NO₂ 218.1176;Found 218.1184; [M+NH₄]⁺ Calcd for C₁₃H₁₉N₂O₂ 235.1441; Found 235.1451;[M+Na]⁺ Calcd for C₁₃H₁₅NO₂Na 240.0995; Found 240.1006. R_(f)=0.4 (20%EtOAc in hexane)

-   -   c.        2-(4-METHYLCYCLOHEX-1-EN-1-YL)-2-(PROP-2-YN-1-YL)MALONONITRILE        (3C).

White solid, 90% yield, 1.12 g. Purified using 10% EtOAc in hexane. ¹HNMR (500 MHz, CDCl₃) δ 6.27 (dq, J=4.4, 2.1 Hz, 1H), 3.02-2.92 (m, 2H),2.36-2.33 (m, 1H), 2.29 (dtd, J=18.0, 4.9, 2.2 Hz, 1H), 2.18 (dh, J=8.7,3.1, 2.5 Hz, 2H), 1.89-1.74 (m, 2H), 1.74-1.64 (m, 1H), 1.33 (dddd,J=13.1, 10.7, 8.8, 6.7 Hz, 1H), 0.99 (d, J=6.5 Hz, 3H). ¹³C NMR (125MHz, CDCl₃) δ 130.55, 126.57, 113.83, 113.64, 75.05, 74.74, 43.00,33.57, 30.20, 28.75, 27.37, 24.26, 21.05. HRMS: (ESI-TOF) m/z: [M+Na]⁺Calcd for C₁₃H₁₄N₂Na 221.1049; Found 221.1052. R_(f)=0.4 (15% EtOAc inhexane)

-   -   d. ETHYL        4-(1,1-DICYANOBUT-3-YN-1-YL)CYCLOHEX-3-ENE-1-CARBOXYLATE (3D).

Pale yellow crystals, 84% yield, 12.61 g. Recrystalized in EtOH. ¹H NMR(500 MHz, CDCl₃) δ 6.31 (dt, J=4.2, 2.1 Hz, 1H), 4.16 (q, J=7.1 Hz, 2H),2.98 (d, J=2.6 Hz, 2H), 2.58 (dddd, J=11.1, 9.0, 5.9, 3.1 Hz, 1H), 2.45(dt, J=8.6, 3.0 Hz, 2H), 2.35 (t, J=2.5 Hz, 1H), 2.32-2.19 (m, 2H), 2.15(dq, J=13.0, 4.3 Hz, 1H), 1.83 (dddd, J=13.1, 10.6, 9.0, 5.9 Hz, 1H),1.26 (t, J=7.1 Hz, 3H). ¹³C NMR (125 MHz, CDCl₃) δ 174.4, 129.3, 126.9,113.6, 113.5, 75.4, 74.6, 60.9, 42.9, 38.1, 28.9, 27.6, 24.8, 23.7,14.3. HRMS: (ESI-TOF) m/z: [M+Na]⁺ Calcd for C₁₅H₁₆N₂O₂Na 279.1104;Found 279.1101. R_(f)=0.54 (30% EtOAc in hexane)

-   -   e. TERT-BUTYL        3-(1,1-DICYANOBUT-3-YN-1-YL)-8-AZABICYCLO[3.2.1]OCT-2        -ENE-8-CARBOXYLATE (3E).

White solid, 95% yield, 2.16 g. Purified using 10% EtOAc in hexane. ¹HNMR (500 MHz, DMSO-d₆) δ 6.56 (d, J=5.3 Hz, 1H), 4.42 (s, 1H), 4.33 (dd,J=7.8, 4.6 Hz, 1H), 3.31 (d, J=2.5 Hz, 2H), 3.25 (t, J=2.5 Hz, 1H),2.81-2.73 (m, 1H), 2.14 (dq, J=13.9, 7.2 Hz, 1H), 2.02 (d, J=17.2 Hz,1H), 1.90 (td, J=7.7, 3.8 Hz, 2H), 1.61 (dt, J=12.2, 7.7 Hz, 1H), 1.44(d, J=7.6 Hz, 1H), 1.41 (s, 9H). ¹³C NMR (125 MHz, DMSO-d₆) δ 152.8,134.5, 125.1, 113.4, 113.2, 78.7, 76.4, 75.6, 52.5, 51.0, 41.3, 33.1,32.2, 28.5, 27.6, 26.8. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₁₈H₂₂N₃O₂334.1526; Found 334.1542. R_(f)=0.3 (20% EtOAc in hexane).

-   -   f.        2-(BICYCLO[3.2.1]OCTA-2,6-DIEN-3-YL)-2-(PROP-2-YN-1-YL)MALONONITRILE        (3F).

White solid, 73% yield, 266 mg. Purified using 10% EtOAc in hexane. ¹HNMR (500 MHz, CDCl₃) δ 6.69 (d, J=6.8 Hz, 1H), 6.22 (dd, J=5.6, 2.8 Hz,1H), 5.81 (dd, J=5.6, 2.8 Hz, 1H), 2.98-2.89 (m, 4H), 2.43 (ddd, J=17.7,5.3, 1.9 Hz, 1H), 2.34 (t, J=2.6 Hz, 1H), 1.99 (dt, J=9.6, 4.6 Hz, 1H),1.92 (d, J=17.6 Hz, 1H), 1.66 (d, J=9.9 Hz, 1H). ¹³C NMR (125 MHz,CDCl₃) δ 139.0, 137.1, 131.2, 123.9, 113.6, 113.5, 75.3, 74.7, 42.8,40.2, 38.6, 37.6, 28.9, 27.4. HRMS: (ESI-TOF) m/z: [M+Na]⁺ Calcd forC₁₄H₁₂N₂Na 231.0893; Found 231.0884. R_(f)=0.43 (20% EtOAc in hexane)

-   -   g. TERT-BUTYL        3-(1,1-DICYANOPENT-3-YN-1-YL)-8-AZABICYCLO[3.2.1]OCT-2-ENE-8-CARBOXYLATE        (3H).

Yellow oil, 85% yield, 303 mg. Purified using 10% EtOAc in hexane. Note:isolated as a 6:1 mixture with unidentified byproduct. ¹H NMR (500 MHz,DMSO-d₆) δ 6.54 (d, J=5.4 Hz, 1H), 4.43 (t, J=5.5 Hz, 1H), 4.34 (dd,J=7.6, 4.6 Hz, 1H), 3.21 (q, J=2.4 Hz, 2H), 2.76 (dd, J=17.6, 4.3 Hz,1H), 2.15 (ddd, J=16.8, 9.7, 4.1 Hz, 1H), 2.01 (d, J=17.5 Hz, 1H), 1.89(dd, J=6.1, 3.1 Hz, 1H), 1.84 (q, J=2.8 Hz, 3H), 1.79 (q, J=2.4 Hz, 1H),1.61 (dt, J=12.9, 8.0 Hz, 1H), 1.42 (s, 9H). ¹³C NMR (125 MHz, DMSO-d₆)δ 152.9, 134.4, 125.3, 113.7, 113.5, 82.1, 78.7, 70.7, 52.5, 51.1, 41.7,33.1, 32.3, 28.6, 27.6, 27.6, 27.4, 2.5. HRMS (ESI-TOF) m/z: [M+Na]⁺Calcd for C₁₉H₂₃N₃O₂Na 348.1682; Found 348.1694. R_(f)=0.31 (20% EtOAcin hexane)

-   -   h. TERT-BUTYL        3-(1,1-DICYANO-4-PHENYLBUT-3-YN-1-YL)-8-AZABICYCLO[3.2.1]OCT-2-ENE-8-CARBOXYLATE        (3I).

Yellow solid, 85% yield, 243 mg. Purified using 10% EtOAc in hexane. ¹HNMR (500MHz, DMSO-d₆) δ 7.52-7.34 (m, 5H), 6.63 (ddd, J=5.6, 2.0, 1.1Hz, 1H), 4.46 (t, J=5.4 Hz, 1H), 4.35 (dd, J=7.0, 5.0 Hz, 2H), 3.59 (d,J=1.8 Hz, 2H), 2.87-2.78 (m, 1H), 2.20-2.05 (m, 2H), 1.94-1.78 (m, 2H),1.68-1.60 (m, 1H), 1.40 (s, 9H). ¹³C NMR (125 MHz, DMSO -d₆) δ 152.8,134.6, 131.0, 128.6, 128.2, 121.2, 113.5, 113.3, 85.4, 81.4, 78.7, 52.5,51.0, 41.5, 33.1, 32.3, 28.6, 27.7, 27.6. HRMS (ESI-TOF) m/z: [M+Na]⁺Calcd for C₂₄H₂₅N₃O₂Na 410.1839; Found 410.1840. *Note: sample wasdissolved in MeOH. R_(f)=0.25 (20% EtOAc in hexane)

-   -   i. TERT-BUTYL        3-(5-ACETOXY-1,1-DICYANOPENT-3-YN-1-YL)-8-AZABICYCLO[3.2.1]OCT-2-ENE-8-CARBOXYLATE        (3J).

Pale yellow oil, 79% yield, 221 mg. Purified using gradient: 10%→20%EtOAc in hexane. ¹H NMR (500 MHz, DMSO-d₆) δ 6.55 (d, J=5.3 Hz, 1H),4.72 (t, J=2.1 Hz, 2H), 4.43 (t, J=4.3 Hz, 1H), 4.34 (dt, J=7.9, 2.8 Hz,1H), 3.39 (q, J=2.3 Hz, 2H), 2.81-2.71 (m, 1H), 2.19-2.09 (m, 1H), 2.04(s, 3H), 2.02-1.97 (m, 1H), 1.90 (ddt, J=8.7, 5.2, 3.2 Hz, 2H), 1.61(dt, J=13.2, 8.1 Hz, 1H), 1.41 (s, 9H). ¹³C NMR (125 MHz, DMSO-d₆) δ169.76, 153.73, 135.50, 125.91, 114.18, 114.02, 81.33, 79.57, 78.91,53.38, 51.93, 51.86, 41.98, 33.89, 33.10, 29.42, 28.45, 27.91, 20.64.HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₁H₂₆N₃O₄ 384.1918; Found384.1936; [M+Na]⁺ Calcd for C₂₁H₂₅N₃O₄Na 406.1737; Found 406.1754.R_(f)=0.13 (20% EtOAc in hexane)

-   -   j.        5-(BICYCLO[3.2.1]OCTA-2,6-DIEN-3-YL)-5,5-DICYANOPENT-2-YN-1-YL        ACETATE (3K).

Yellow oil, 63% yield, 311 mg. Purified using 10% EtOAc in hexane. ¹HNMR (500 MHz, CDCl₃) δ 6.68 (d, J=6.4 Hz, 1H), 6.21 (dt, J=5.7, 2.6 Hz,1H), 5.80 (dt, J=5.7, 2.4 Hz, 1H), 4.69 (dd, J=14.5, 3.2 Hz, 2H), 2.94(bs, 4H), 2.42 (ddt, J=17.7, 4.6, 2.3 Hz, 1H), 2.09 (d, J=3.1 Hz, 3H),2.06-1.95 (m, 1H), 1.91 (d, J=17.6 Hz, 1H), 1.65 (dd, J=9.6, 2.4 Hz,1H). ¹³C NMR (125 MHz, CDCl₃) δ 170.2, 139.0, 137.2, 131.3, 124.0,113.6, 113.5, 81.3, 77.5, 52.0, 42.8, 40.2, 38.6, 37.7, 29.3, 27.4,20.8. HRMS: (ESI-TOF) m/z: [M+H⁺ Calcd for C₁₇H₁₇N₂O₂ 281.1285; Found281.1288. R_(f)=0.37 (20% EtOAc in hexane)

-   -   k. N-(4-(1,1-DICYANOBUT-3-YN-1-YL)CYCLOHEX-3-EN-1-YL)ACETAMIDE        (3L).

Pale orange crystals, 72% yield, 1.7 g. Recrystalized in EtOH. ¹H NMR(500 MHz, Methanol-d₄) δ 6.25 (ddt, J=4.6, 3.1, 1.5 Hz, 1H), 3.95 (dddd,J=10.4, 8.7, 5.5, 3.1 Hz, 1H), 3.25-3.13 (m, 2H), 2.85 (t, J=2.6 Hz,1H), 2.59-2.49 (m, 1H), 2.35 (tdt, J=7.0, 4.2, 2.1 Hz, 2H), 2.17-1.93(m, 5H), 1.69 (dddd, J=12.9, 10.5, 8.2, 6.9 Hz, 1H). ¹³C NMR (125 MHz,CD₃OD) δ 171.5, 127.9, 127.5, 113.8, 113.6, 75.2, 74.7, 43.9, 43.0,30.7, 27.7, 27.4, 22.9, 21.3. HRMS: (ESI-TOF) m/z: [M+H]⁺ Calcd forC₁₄H₁₆N₃O 242.1288; Found 242.1293.

-   -   l.        2-(PROP-2-YN-1-YL)-2-(1,4-DIOXASPIRO[4.5]DEC-7-EN-8-YL)MALONONITRILE        (3M).

White solid, 96% yield, 5.9 g. Purified using 10% EtOAc in hexane. ¹HNMR (500MHz, CDCl₃) δ 6.19 (t, J=3.8 Hz, 1H), 3.98 (t, J=2.7 Hz, 4H),2.98 (d, J=2.6 Hz, 2H), 2.45-2.36 (m, 5H), 1.85 (t, J=6.4 Hz, 2H). 13CNMR (126 MHz, cdcl3) δ 128.4, 126.9, 113.6, 106.5, 75.5, 74.7, 64.7,43.0, 36.0, 30.9, 29.2, 24.1. HRMS: (ESI-TOF) m/z: [M+NH₄]⁺ Calcd forC₁₄H₁₄N₂O₂Na 260.1394; Found 260.1390.

6. General Procedure for One-Pot Cope/α-Alkylation.

Enyne 3 was dissolved in toluene (unless otherwise specified) and N₂ wasbubbled through the solution for five minutes. The solution was thenheated using a pre-heated pie -block or oil bath in a screw cap pressureflask (temperatures and times are listed in Table 1). When the reactionwas done, the solution was cooled to room temperature and the solventwas removed under reduced pressure. The percent conversion wascalculated using ¹H NMR (chemical shifts used for this determination areoutlined in Table 1) and this was used to determine the stoichiometryfor the propargylation step. The crude product from the Coperearrangement was then re-dissolved in THF (0.5M with respect to allene4) and added to a suspension of NaH (1.1 equivalent) in THF at 0° C. Thepropargyl bromide derivative 2′ was then immediately added to thesolution and the reaction was warmed to room temperature. Uponcompletion of the reaction (monitored by TLC), a saturated solution ofNH₄Cl was added to quench the NaH and the crude material was taken up inethyl acetate. The solution was then washed with H₂O and brine, driedwith Na₂SO₄, and concentrated under reduced pressure. The compound waspurified via column chromatography (hexane-ethyl acetate). Reactiontemperatures, times, and conversion for enyne Cope rearrangement basedon the enyne used in the reaction are given below in Table 7. Using theforegoing method, compounds 5 aa, 5 ac, 5 aa, 5 ad, 5 bd, 5 cd, 5 dd, 5de, 5 ed, 5 fd, 5 hd, 5 id, 5 jd, 5 kd, 8 a-8 b, and 8 e were prepared,and are described in further detail herein below.

TABLE 7 Temp Time % conversion H_(enyne) H_(allene) Enyne (° C.) (hrs.)(3 to 4) (ppm) (ppm) 3a 150 15 85 6.31 5.15, 4.88 3b 170 6 37 6.11 5.17,4.84 3c 150 4.5 61 6.27 5.16, 4.88 3d 150 1.5 56 6.34 5.23, 4.88 3e 1501 100 6.55 5.33, 4.86 3f 150 2.5 91 6.68 5.22, 4.90 3h 200 1.5 100 6.574.71 3i 200 1.5 71 6.65 5.20 3j 200 1.5 88 6.61 4.93 3k 200 1.5 85 6.674.98

-   -   a.        2-(6-(2λ5-PROPA-1,2-DIEN-1-YL)CYCLOHEX-1-EN-1-YL)-2-(PROP-2-YN-1        -YL)MALONONITRILE (5AA).

Pale yellow oil, 35% yield, 300 mg. Purified using 2% EtOAc in hexane,but could not be separated from unreacted enyne starting material. ¹HNMR (500 MHz, CDCl₃) δ 6.36 (t, J=3.9 Hz, 1H), 5.19 (dd, J=14.8, 6.6 Hz,1H), 4.83 (dt, J=6.5, 2.0 Hz, 2H), 3.12 (dd, J=16.6, 2.6 Hz, 1H), 3.07(m, 1H), 3.01 (dd, J=16.7, 2.6 Hz, 1H), 2.35 (t, J=2.5 Hz, 1H),2.28-2.10 (m, 2H), 1.85-1.55 (m, 4H). ¹³C NMR (125 MHz, CDCl₃) δ 209.2,133.0, 128.9, 114.4, 114.2, 92.7, 77.2, 75.3, 75.1, 42.7, 35.8, 30.5,29.8, 25.4, 16.8. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₁₅H₁₅N₂223.1230; Found 223.1223. R_(f)=0.51 (20% EtOAc in hexane). Note:Cyclohexane was used as solvent for Cope rearrangement rather thantoluene.

-   -   b.        2-(6-(2λ5-PROPA-1,2-DIEN-1-YL)CYCLOHEX-1-EN-1-YL)-2-(BUT-2-YN-1-YL)MALONONITRILE        (5AB).

Pale yellow oil, 20% yield, 182 mg. Purified using 3% EtOAc in hexane,but could not be fully separated from minor impurities from the Coperearrangement. ¹H NMR (500 MHz, CDCl₃) δ 6.32 (dd, J=3.2, 3.5 Hz, 1H),5.22-5.13 (m, 1H), 4.82 (dd, J=6.8, 2.5 Hz, 2H), 3.12-2.81 (m, 3H),2.28-2.03 (m, 2H), 2.01-1.53 (m, 8H). ¹³C NMR (125 MHz, CDCl₃) δ 209.2,132.5, 129.5, 114.8, 114.7, 92.8, 82.9, 77.4, 77.2, 77.2, 76.9, 70.6,43.3, 35.8, 31.1, 29.9, 25.5, 16.9, 3.7. HRMS (ESI-TOF) m/z: [M+H]⁺Calcd for C₁₆H₁₇N₂ 237.1386; Found 237.1386. R_(f)=0.39 (10% EtOAc inhexane). Note: Cyclohexane was used as solvent for Cope rearrangementrather than toluene.

-   -   c.        2-(6-(2λ5-PROPA-1,2-DIEN-1-YL)CYCLOHEX-1-EN-1-YL)-2-(3-PHENYLPROP-2-YN-1-YL)MALONONITRILE        (5AC).

Pale yellow oil, 25% yield, 255 mg. Purified using 3% EtOAc in hexane.¹H NMR (600MHz, CDCl₃) δ 7.50-7.41 (m, 2H), 7.38-7.28 (m, 3H), 6.41 (t,J=3.9 Hz, 1H), 5.23 (dt, J=8.0, 6.6 Hz, 1H), 4.86 (dtd, J=6.5, 3.6, 3.0,1.8 Hz, 2H), 3.36 (d, J=16.7 Hz, 1H), 3.24 (d, J=16.7 Hz, 1H), 3.14 (s,1H), 2.29-2.12 (m, 2H), 1.86-1.61 (m, 4H). ¹³C NMR (150 MHz, CDCl₃) δ209.3, 132.9, 132.0, 129.2, 129.0, 128.5, 122.1, 114.7, 114.5, 92.8,86.9, 80.6, 77.3, 43.0, 35.9, 31.6, 29.9, 25.5, 16.9. HRMS (ESI-TOF)m/z: [M+Na]⁺ Calcd for C₂₁H₁₈N₂Na 321.1362; Found 321.1376. R_(f)=0.42(10% EtOAc in hexane). Note: Cyclohexane was used as solvent for Coperearrangement rather than toluene.

-   -   d.        5-(6-(2λ5-PROPA-1,2-DIEN-1-YL)CYCLOHEX-1-EN-1-YL)-5,5-DICYANOPENT-2-YN-1-YL        ACETATE (5AD).

Pale yellow oil, 21% yield, 233 mg. Purified using gradient: 3%→10%EtOAc in hexane. ¹H NMR (500 MHz, CDCl₃) δ 6.35 (t, J=3.9 Hz, 1H), 5.18(q, J=7.0 Hz, 1H), 4.83 (dt, J=6.6, 2.0 Hz, 2H), 4.70 (t, J=2.1 Hz, 2H),3.16 (dt, J=16.6, 2.1 Hz, 1H), 3.09-2.98 (m, 2H), 2.28-2.07 (m, 5H),1.85-1.57 (m, 4H). ¹³C NMR (125 MHz, CDCl₃) δ 209.2, 170.2, 133.1,129.0, 114.4, 114.2, 92.7, 80.9, 78.2, 77.3, 52.1, 42.7, 35.9, 30.9,29.9, 25.5, 20.8, 16.8. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₁₈H₁₉N₂O₂295.1441; Found 295.1444; [M+NH₄]⁺ Calcd for C₁₈H₂₂N₃O₂ 312.1707; Found312.1717; [M+Na]⁺ Calcd for C₁₈H₁₈N₂O₂Na 317.1260; Found 317.1266.R_(f)=0.41 (20% EtOAc in hexane). Note: Cyclohexane was used as solventfor Cope rearrangement rather than toluene.

-   -   e. METHYL        2-(6-(2λ5-PROPA-1,2-DIEN-1-YL)CYCLOHEX-1-EN-1-YL)-6-ACETOXY-2-CYANOHEX-4-YNOATE        (5BD).

Pale yellow oil, 25% yield, 38 mg, d.r.=1:1.2. Purified using gradient:5%→10% EtOAc in hexane. ¹H NMR (500 MHz, CDCl₃): Diastereomer 1: δ 6.22(s, 1H), 5.03 (dd, J=14.8, 6.8 Hz, 2H), 4.72 (m, 2H), 4.66 (m, 2H), 3.79(s, 3H), 3.03-2.93 (m, 3H), 2.20-2.10 (m, 2H), 2.08 (s, 3H), 1.76-1.60(m, 4H); Diastereomer 2: δ 6.10 (s, 1H), 5.13 (dd, J=14.9, 6.7 Hz, 2H),4.74 (m, 2H), 4.66 (m, 2H), 3.82 (s, 3H), 3.09-2.93 (m, 3H), 2.20-2.10(m, 2H), 2.08 (s, 3H), 1.76-1.60 (m, 4H). ¹³C NMR (125 MHz, CDCl₃):Diastereomer 1: δ 208.6, 170.3, 167.1, 131.5, 130.8, 117.8, 92.6, 80.7,78.7, 76.5, 54.0, 53.9, 52.4, 34.8, 30.0, 27.1, 25.5, 20.9, 16.9;Diastereomer 2: δ 208.7, 170.3, 167.4, 131.5, 130.2, 117.8, 93.0, 80.7,78.5, 76.5, 54.4, 54.0, 52.4, 36.0, 29.9, 27.7, 25.4, 20.9, 16.9. HRMS(ESI-TOF) m/z: [M+Na]⁺ Calcd for C₁₉H₂₁NO₄Na 350.1363; Found 350.1380.R_(f)=0.33 (20% EtOAc in hexane).

-   -   f.        5,5-DICYANO-5-(4-METHYL-6-(2λ5-PROPA-1,2-DIEN-1-YL)CYCLOHEX-1-EN-1-YL)PENT-2-YN-1-YL        ACETATE (5CD).

Yellow oil, 38% yield, 39 mg, d.r>20:1. Purified using 5% EtOAc inhexane. ¹H NMR (500 MHz, CDCl₃) δ 6.30 (dd, J=4.8, 2.8 Hz, 1H), 5.20(dd, J=14.6, 6.7 Hz, 1H), 4.84-4.79 (m, 2H), 4.68 (t, J=2.1 Hz, 2H),3.15 (dt, J=16.6, 2.1 Hz, 1H), 3.08 (m, 1H), 3.02 (dt, J=16.6, 2.1 Hz,1H), 2.30 (dt, J=18.7, 5.0 Hz, 1H), 2.08 (s, 3H), 1.87 (m, 1H),1.79-1.70 (m, 2H), 1.47 (td, J=12.6, 5.1 Hz, 1H), 0.98 (d, J=6.6 Hz,3H). ¹³C NMR (125 MHz, CDCl₃) δ 209.0, 170.2, 133.0, 128.9, 114.4,114.2, 93.1, 81.0, 78.2, 77.4, 52.1, 42.5, 38.2, 36.6, 34.1, 31.1, 22.8,21.5, 20.8. HRMS: (ESI-TOF) m/z: [M+Na]⁺ Calcd for C₁₉H₂₀N₂O₂Na331.1417; Found 331.1432; [2M+Na]⁺ Calcd for C₁₉H₂₀N₂O₂639.2942; Found639.2958. R_(f)=0.14 (10% EtOAc in hexane). Relative stereochemistry wasdetermined by analysis of 6 cd.

-   -   g. ETHYL        4-(5-ACETOXY-1,1-DICYANOPENT-3-YN-1-YL)-5-(2λ5-PROPA-1,2-DIEN-1        -YL)CYCLOHEX-3-ENE-1-CARBOXY LATE (5DD).

Yellow oil, 24% yield (679 mg) +29% recovered enyne starting material,d.r.>20:1. Purified using 15% EtOAc in hexane. ¹H NMR (500 MHz, CDCl₃) δ6.34 (dd, J=4.7, 3.0 Hz, 1H), 5.24 (q, J=6.8 Hz, 1H), 4.89 (qdd, J=11.2,6.6, 2.1 Hz, 2H), 4.69 (t, J=2.0 Hz, 2H), 4.16 (q, J=7.2 Hz, 2H),3.21-3.11 (m, 2H), 3.05 (dt, J=16.7, 2.1 Hz, 1H), 2.75 (dddd, J=13.3,9.9, 6.1, 3.1 Hz, 1H), 2.51 (dt, J=19.1, 5.4 Hz, 1H), 2.39 (ddt, J=19.0,10.7, 2.3 Hz, 1H), 2.10 (s, 4H), 1.86 (td, J=12.9, 4.9 Hz, 1H), 1.27 (t,J=7.2 Hz, 3H). ¹³C NMR (125 MHz, CDCl₃) δ 209.17, 174.62, 170.08,131.14, 128.88, 114.06, 113.77, 92.12, 81.18, 78.04, 77.73, 60.85,51.91, 41.96, 35.53, 33.86, 31.99, 31.24, 27.75, 20.64, 14.22. HRMS:(ESI-TOF) m/z: [M+Na]⁺ Calcd for C₂₁H₂₂N₂O₄Na 367.1652; Found 367.1634.R_(f)=0.38 (30% EtOAc in hexane). Relative stereochemistry was assumedto be consistent with the results for 5 cd.

-   -   h. ETHYL        4-(1,1-DICYANO-4-(TRIMETHYLSILYL)BUT-3-YN-1-YL)-5-(2λ5-PROPA-1,2-DIEN-1-YL)CYCLOHEX-3-ENE-1-CARBOXY        LATE (5DE).

Pale yellow solid, 24% yield (641 mg) +37% recovered enyne startingmaterial (744 mg), d.r.>20:1. Purified using 5% EtOAc in hexane. ¹H NMR(500 MHz, CDCl₃) δ 6.33 (dd, J=4.7, 3.0 Hz, 1H), 5.24 (q, J=6.8 Hz, 1H),4.96-4.83 (m, 2H), 4.17 (q, J=7.1 Hz, 2H), 3.21-3.16 (m, 1H), 3.12 (d,J=16.7 Hz, 1H), 3.02 (d, J=16.8 Hz, 1H), 2.75 (dtd, J=13.2, 6.4, 6.0,3.1 Hz, 1H), 2.50 (dt, J=19.0, 5.5 Hz, 1H), 2.43-2.34 (m, 1H), 2.12 (dt,J=13.2, 2.8 Hz, 1H), 1.85 (td, J=12.9, 4.9 Hz, 1H), 1.28 (t, J=7.1 Hz,3H), 0.18 (s, 9H). ¹³C NMR (125 MHz, CDCl₃) δ 209.34, 174.83, 130.96,129.21, 114.32, 113.98, 110.13, 96.50, 93.12, 92.28, 78.17, 77.41,77.16, 76.91, 60.98, 42.19, 35.71, 34.03, 32.40, 32.14, 27.87, 14.36,−0.20. HRMS: (ESI-TOF) m/z: [M+NH₄]⁺ Calcd for C₂₁ H₃₀N₃O₂Si 384.2102;Found 384.2090; [M+Na]⁺ Calcd for C₂₁ H₂₆N₂O₂SiNa 389.1656; Found389.1648. R_(f)=0.5 (20% EtOAc in hexane). Relative stereochemistry wasassumed to be consistent with the results for 5 cd.

-   -   i. TERT-BUTYL        3-(5-ACETOXY-1,1-DICYANOPENT-3-YN-1-YL)-4-(2λ5-PROPA-1,2-DIEN-1-YL)-8-AZABICYCLO[3.2.1]OCT-2-ENE-8-CARBOXYLATE        (5ED).

Pale yellow oil, 48% yield, 194 mg, d.r.>20:1. Purified using 10% EtOAcin hexane. ¹H NMR (500 MHz, DMSO-d₆) δ 6.54 (d, J=5.4 Hz, 1H), 5.24 (dd,J=14.9, 6.6 Hz, 1H), 4.88 (ddd, J=11.0, 6.6, 1.6 Hz, 1H), 4.78 (ddd,J=11.0, 6.6, 1.6 Hz, 1H), 4.73 (t, J=2.1 Hz, 2H), 4.54 (t, J=5.6 Hz,1H), 4.33 (d, J=7.8 Hz, 1H), 3.42 (ddt, J=30.0, 17.1, 2.1 Hz, 2H), 2.91(d, J=8.1 Hz, 1H), 2.03 (s, 4H), 1.83 (t, J=10.7 Hz, 1H), 1.72 (dq,J=11.2, 6.0, 5.3 Hz, 1H), 1.65-1.57(m, 1H), 1.40 (s, 9H). ¹³C NMR (125MHz, DMSO-d₆) δ 209.3, 169.8, 152.8, 135.4, 127.7, 114.8, 114.4, 91.2,81.3, 79.4, 79.2, 77.5, 57.4, 53.1, 51.9, 46.4, 40.6, 33.4, 29.7, 28.6,27.9, 20.7. HRMS: (ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₄H₂₈N₃O₄ 444.1894;Found 444.1913. R_(f)=0.24 (20% EtOAc in hexane). Relativestereochemistry was determined by analysis of 9.

-   -   j.        5-(4-(2λ5-PROPA-1,2-DIEN-1-YL)BICYCLO[3.2.1]OCTA-2,6-DIEN-3-YL)-5,5-DICYANOPENT-2-YN-1-YL        ACETATE (5FD).

Pale yellow oil, 56% yield, 86 mg, d.r.>20:1. Purified using 7% EtOAc inhexane. ¹H NMR (500 MHz, CDCl₃) δ 6.77 (d, J=6.6 Hz, 1H), 6.35 (dd,J=5.6, 2.9 Hz, 1H), 5.86 (dd, J=5.6, 2.9 Hz, 1H), 5.28 (dt, J=9.5, 6.6Hz, 1H), 4.97-4.84 (m, 2H), 4.68 (t, J=2.1 Hz, 2H), 3.12 (dt, J=16.7,2.1 Hz, 2H), 3.05 (dt, J=16.7, 2.1 Hz, 1H), 2.95 (m, 1H), 2.79 (m, 2H),2.10 (s, 3H), 1.91-1.81 (m, 2H). ¹³C NMR (125 MHz, CDCl₃) δ 209.4,170.2, 141.5, 140.0, 131.3, 125.8, 114.3, 114.1, 92.1, 81.1, 77.9, 77.2,52.1, 46.0, 41.9, 39.7, 39.1, 36.2, 30.2, 20.8. HRMS: (ESI-TOF) m/z:[M+H]⁺ Calcd for C₂₀H₁₉N₂O₂ 319.1441; Found 319.1447; [M+NH₄]⁺ Calcd forC₂₀H₂₂N₃O₂ 336.1707; Found 336.1719; [M+Na]⁺ Calcd for C₂₀H₁₈N₂O₂Na341.1260; Found 341.1270. R_(f)=0.28 (20% EtOAc in hexane). Relativestereochemistry was determined by analysis of 10c

-   -   k. TERT-BUTYL 3-(5-ACETOXY-1,1        -DICYANOPENT-3-YN-1-YL)-4-(3λ5-BUTA-2,3-DIEN-2-YL)-8-AZABICYCLO[3.2.1]OCT-2-ENE-8-CARBOXYLATE        (5HD).

Pale yellow oil, 59% yield, 78 mg, d.r.>20:1. Purified using 20% EtOAcin hexane. ¹H NMR (500 MHz, DMSO-d₆) δ 6.50 (d, J=5.3 Hz, 1H), 4.75 (m,3H), 4.59 (ddd, J=9.9, 3.5, 1.9 Hz, 1H), 4.51 (t, J=5.5 Hz, 1H), 4.43(d, J=7.7 Hz, 1H), 3.46 (dt, J=16.9, 2.1 Hz, 1H), 3.39 (dt, J=16.9, 2.1Hz, 1H), 2.69 (d, J=2.2 Hz, 1H), 2.15-2.04 (m, 1H), 2.04 (s, 3H), 1.81(h, J=3.3, 2.8 Hz, 4H), 1.74 (dq, J=11.4, 6.0, 5.4 Hz, 1H), 1.62 (dt,J=15.4, 8.3 Hz, 1H), 1.41 (s, 9H). ¹³C NMR (125 MHz, DMSO-d₆) δ 208.41,169.83, 152.02, 134.34, 128.01, 114.97, 114.23, 99.22, 81.15, 79.46,79.00, 77.12, 54.38, 51.94, 50.89, 36.84, 33.64, 30.92, 28.59, 27.95,24.73, 20.70, 17.67. HRMS: (ESI-TOF) m/z: [M+Na]⁺ Calcd for C₂₆H₂₉N₃O₄Na458.2050; Found 458.2052. R_(f)=0.48 (50% EtOAc in hexane). Relativestereochemistry was determined by analysis of 9.

-   -   l. TERT-BUTYL        3-(5-ACETOXY-1,1-DICYANOPENT-3-YN-1-YL)-4-(1-PHENYL-2λ5-PROPA-1,2-DIEN-1-YL)-8-AZABICYCLO[3.2.1]OCT-2-ENE-8-CARBOXYLATE        (5ID).

Yellow oil, 41% yield, 53 mg (+45% recovered starting material),d.r.>20:1. Purified using 20% EtOAc in hexane. ¹H NMR (500 MHz, DMSO-d₆)δ 7.51 (d, J=7.8 Hz, 2H), 7.40 (t, J=7.8 Hz, 2H), 7.27 (t, J=7.4 Hz,1H), 6.61 (d, J=5.3 Hz, 1H), 5.22 (d, J=12.2 Hz, 1H), 5.05 (d, J=12.0Hz, 1H), 4.77 (t, J=2.1 Hz, 2H), 4.58 (t, J=5.3 Hz, 1H), 4.37 (d, J=8.0Hz, 1H), 3.60-3.43 (m, 3H), 2.16-2.06 (m, 1H), 2.05 (s, 3H), 1.93-1.85(m, 1H), 1.81-1.71 (m, 2H), 1.36-1.20 (bs, 9H). ¹³C NMR (125 MHz,DMSO-d₆) δ 209.4, 169.0, 151.1, 134.1, 128.0, 126.9, 126.6, 125.9,114.1, 113.3, 105.3, 80.4, 78.6, 78.1, 54.5, 51.7, 51.1, 46.1, 40.0,39.9, 39.7, 39.5, 39.4, 39.2, 39.0, 36.0, 32.9, 30.2, 27.5, 26.9, 19.8.HRMS: (ESI-TOF) m/z: [M +Calcd for C₃₀H₃₁N₃O₄Na 520.2207; Found520.2232. R_(f)=0.28 (30% EtOAc in hexane). Relative stereochemistry wasdetermined by analysis of 9.

-   -   m. TERT-BUTYL        3-(5-ACETOXY-1,1-DICYANOPENT-3-YN-1-YL)-4-(1-ACETOXY-3L5-BUTA-2,3-DIEN-2-YL)-8-AZABICYCLO[3.2.1]OCT-2-ENE-8-CARBOXYLATE        (5JD).

Yellow oil, 44% yield, 57 mg, d.r.>20:1. Purified using 25% EtOAc inhexane. ¹H NMR (500 MHz, DMSO-d₆) δ 6.55 (d, J=5.3 Hz, 1H), 4.97 (dd,J=11.2, 2.1 Hz, 1H), 4.80 (dd, J=11.3, 1.9 Hz, 1H), 4.74 (s, 2H), 4.72(dt, J=12.6, 2.5 Hz, 1H), 4.66 (dt, J=12.6, 2.5 Hz, 1H), 4.54 (t, J=5.5Hz, 1H), 4.48 (d, J=7.9 Hz, 1H), 3.49 (dt, J=16.9.4, 2.0 Hz, 1H), 3.41(dt, J=16.9, 1.9 Hz, 1H), 2.87 (s, 1H), 2.04 (m, 7H), 1.84 (t, J=10.4Hz, 1H), 1.74 (dq, J=11.9, 6.2, 5.8 Hz, 1H), 1.62 (dt, J=15.2, 8.1 Hz,1H), 1.41 (s, 9H). ¹³C NMR (125 MHz, DMSO-d₆) δ 208.86, 170.25, 169.83,152.12, 135.18, 127.04, 114.88, 114.14, 100.30, 81.23, 79.54, 79.38,79.19, 63.25, 55.23, 51.92, 47.10, 40.65, 40.48, 33.64, 30.52, 28.54,27.78, 20.98, 20.69. HRMS: (DART) m/z: [M+H]⁺ Calcd for C₂₇H₃₂N₃O₆494.2286; Found 494.2278. R_(f)=0.54 (50% EtOAc in hexane). Relativestereochemistry was determined by analysis of 9.

-   -   n.        2-(3-(5-ACETOXY-1,1-DICYANOPENT-3-YN-1-YL)BICYCLO[3.2.1]OCTA-3,6-DIEN-2-YL)-3λ5-BUTA-2,3-DIEN-1-YL        ACETATE (5KD).

Yellow oil, 53% yield, 418 mg, d.r.>20:1. Purified using 15% EtOAc inhexane. ¹H NMR (500 MHz, CDCl₃) δ 6.76 (dt, J=6.7, 1.0 Hz, 1H), 6.36(dd, J=5.5, 2.8 Hz, 1H), 5.83 (dd, J=5.5, 3.0 Hz, 1H), 5.10 (m, 1H),5.01 (m, 1H), 4.76-4.67 (m, 4H), 3.12 (dt, J=16.7, 2.1 Hz, 1H), 2.99(dt, J=16.7, 2.1 Hz, 1H), 2.95-2.91 (m, 2H), 2.62 (p, J=1.3 Hz, 1H),2.10 (d, J=5.0 Hz, 6H), 1.97 (d, J=10.3 Hz, 1H), 1.79 (dt, J=9.8, 4.7Hz, 1H). ¹³C NMR (125 MHz, CDCl₃) δ 208.5, 170.8, 170.2, 142.3, 140.3,131.1, 125.3, 114.4, 114.1, 101.6, 81.1, 80.5, 78.0, 64.3, 52.0, 44.7,41.3, 40.7, 39.0, 35.4, 31.1, 21.1, 20.8. HRMS: (ESI-TOF) m/z: [M+Na]⁺Calcd for C₂₃H₂₂N₂O₄Na 413.1472; Found 413.1454. R_(f)=0.4 (30% EtOAc inhexane). Relative stereochemistry was determined by analysis of 10c.

-   -   o. TERT-BUTYL        (E)-3-(1,1-DICYANO-4-PHENYLBUT-3-EN-1-YL)-4-(2λ5-PROPA-1,2-DIEN-1-YL)-8-AZABICYCLO[3.2.1]OCT-2-ENE-8-CARBOXYLATE        (8A).

Pale yellow oil, 60% yield, 248 mg. Purified using 10% EtOAc in hexane.¹H NMR (500 MHz, DMSO-d₆) δ 7.45 (m, 2H), 7.41-7.35 (m, 2H), 7.33-7.28(m, 1H), 6.78 (d, J=15.7 Hz, 1H), 6.55 (d, J=5.5, 1H), 6.17 (dt, J=15.7,7.3 Hz, 1H), 5.29 (dt, J=8.2, 6.6 Hz, 1H), 4.91 (ddd, J=11.0, 6.7, 1.6Hz, 1H), 4.83 (ddd, J=11.1, 6.6, 1.4 Hz, 1H), 4.57 (t, J=5.8, 1H), 4.36(d, J=9.0, 1H), 3.18 (ddd, J=7.4, 2.5, 1.3 Hz, 2H), 2.95 (d, J=8.3, 1H),2.12 -2.01 (m, 1H), 1.81 (m, 1H), 1.73 (m, 1H), 1.62-1.53 (m, 1H), 1.42(s, 9H). ¹³C NMR (125 MHz, DMSO-d₆) δ 208.4, 151.9, 136.5, 135.6, 134.0,127.8, 127.4, 126.0, 119.9, 114.5, 114.1, 90.5, 78.6, 76.6, 56.6, 52.2,45.7, 40.8, 32.6, 27.7, 27.6, 27.1. HRMS: (ESI-TOF) m/z: [M+Na]⁺ Calcdfor C₂₇H₂₉N₃O₂Na 450.2152; Found 450.2167. R_(f)=0.22 (20% EtOAc inhexane). Relative stereochemistry was determined by analysis of 9.

-   -   p. TERT-BUTYL        (E)-3-(2-(λ2-AZANYLIDENE)-1-CYANO-2λ3-ETHYLIDENE)-2-CINNAMYL-4-(2λ5-PROPA-1,2-DIEN-1-YL)-8-AZABICYCLO[3.2.1]OCTANE-8-CARBOXYLATE        (8B).

White solid, 23% yield, 94 mg. Purified using 10% EtOAc in hexane. ¹HNMR (500 MHz, DMSO-d₆) δ 7.43-7.38 (m, 2H), 7.36-7.31 (m, 2H), 7.27-7.22(m, 1H), 6.52 (d, J=15.8 Hz, 1H), 6.27 (dt, J=15.8, 7.2 Hz, 1H), 5.40(td, J=6.7, 5.5 Hz, 1H), 5.02 (ddd, J=11.7, 6.8, 3.7 Hz, 1H), 4.95 (ddd,J=11.7, 6.7, 3.7 Hz, 1H), 4.47 (t, J=6.5 Hz, 2H), 3.68 (m, 1H), 2.99(ddd, J=7.6, 6.1, 1.5 Hz, 1H), 2.66 (dddd, J=14.2, 8.6, 7.2, 1.3 Hz,1H), 2.41-2.29 (m, 1H), 1.92 (ddt, J=7.3, 5.7, 2.5 Hz, 2H), 1.65-1.53(m, 2H), 1.45 (s, 9H). ¹³C NMR (125 MHz, DMSO-d₆) δ 207.5, 180.9, 152.8,136.5, 132.4, 128.1, 128.0, 127.7, 126.9, 126.0, 125.6, 111.1, 111.1,89.0, 88.6, 79.1, 78.3, 56.6, 55.0, 50.2, 48.0, 36.9, 28.1, 27.7, 27.5.HRMS: (ESI -TOF) m/z: [M+Na]⁺ Calcd for C₂₇H₂₉N₃O₂Na 450.2152; Found450.2169. R_(f)=0.3 (20% EtOAc in hexane). Relative stereochemistry wasdetermined by analysis of 8 c.

-   -   q. TERT-BUTYL        3-(1,1-DICYANO-2-(5-(METHOXYCARBONYL)FURAN-2-YL)ETHYL)        -4-(2λ5-PROPA-1,2-DIEN-1-YL)-8-AZABICYCLO[3.2.1]OCT-2-ENE-8-CARBOXYLATE(8E).

Colorless oil, 30% yield, 42.2 mg, d.r.>20:1. Purified using 25% EtOAcin hexane. ¹H NMR (500 MHz, DMSO-d₆) δ 7.29 (d, J=3.4 Hz, 1H), 6.69 (d,J=3.5 Hz, 1H), 6.54 (d, J=5.5 Hz, 1H), 5.28 (q, J=7.1 Hz, 1H), 4.91 (dd,J=11.2, 6.7 Hz, 1H), 4.83 (dd, J=11.1, 6.7 Hz, 1H), 4.54 (t, J=5.7 Hz,1H), 4.35 (d, J=8.0 Hz, 1H), 3.84 (d, J=11.6 Hz, 5H), 2.94 (d, J=8.4 Hz,1H), 2.08-1.97 (m, 1H), 1.82-1.75 (m, 1H), 1.71 (dq, J=11.4, 6.0, 5.4Hz, 1H), 1.56 (dt, J=14.8, 7.9 Hz, 1H), 1.42 (s, 9H). ¹³C NMR (125 MHz,DMSO-d₆) δ 209.30, 158.40, 152.25, 144.73, 135.29, 128.04, 119.49,114.95, 114.50, 113.39, 91.28, 79.42, 77.55, 57.41, 52.15, 46.64, 40.82,36.77, 33.25, 28.56, 27.85.HRMS: (ESI-TOF) m/z: [M+Na]⁺ Calcd forC₂₅H₂₇N₃O₅Na 472.1843; Found 472.1846. R_(f)=0.32 (30% EtOAc in hexane).Relative stereochemistry was determined by analysis of 9.

-   -   r. TERT-BUTYL        (E)-3-(2-(λ2-AZANYLIDENE)-1-CYANO-2λ3-ETHYLIDENE)-2-((5-(METHOXYCARBONYL)FURAN-2-YL)METHYL)-4-(2A5-PROPA-1,2-DIEN-1-YL)-8-AZABICYCLO[3.2.1]OCTANE-8-CARBOXYLATE        (8F).

Yellow solid, 20% yield, 27.4 mg, d.r.>20:1. Purified using 25% EtOAc inhexane. ¹H NMR (500 MHz, DMSO-d₆) δ 7.23 (d, J=3.6, 1H), 6.47 (d, J=3.4Hz, 1H), 5.43 (m, 1.1 Hz, 1H), 5.11-5.00 (m, 2H), 4.49 (d, J=4.7 Hz,1H), 4.42 (d, J=5.5 Hz, 1H), 3.81 (s, 3H), 3.70 (m, 1H), 3.22-3.13 (m,2H), 2.92-2.82 (m, 1H), 1.97-1.88 (m, 2H), 1.68-1.53 (m, 2H), 1.44 (s,9H). ¹³C NMR (125 MHz, DMSO-d₆) δ 207.5, 178.8, 157.8, 155.8, 152.9,142.9, 118.8, 111.0, 110.3, 110.0, 89.5, 88.9, 79.3, 78.4, 56.7, 55.6,51.0, 48.3, 47.9, 40.0, 39.9, 39.7, 39.5, 39.4, 39.2, 39.0, 31.6, 27.8,27.6, 27.4. HRMS: (ESI-TOF) m/z: [M+NH₄]⁺ Calcd for C₂₆H₃₁ N₄O₆367.2289; Found 367.2310. R_(f)=0.48 (30% EtOAc in hexane). Relativestereochemistry was determined by analysis of 8 c.

7. General Procedure for One-Pot Cope/Alkylidene Reduction/α-Alkylation.

Enyne 3 was dissolved in toluene and 2 equivalents of Hantzsch esterwere added. The solution was then heated using a pre-heated pie-block ina screw cap pressure flask (temperatures and times are listed in Table2). When the reaction was done, the solution was cooled to roomtemperature and the solvent was removed under reduced pressure. Thecrude product from the Cope rearrangement was then re-dissolved in DMF(0.3 M with respect to allene 4) and added to a suspension of K₂CO₃ (3equivalent) in DMF. The propargyl bromide derivative 2′ was thenimmediately added to the solution and the reaction was warmed to roomtemperature. Upon completion of the reaction (monitored by TLC), thecrude material was taken up in ethyl acetate. The solution was thenwashed with H₂O (×3) and brine, dried with Na₂SO₄, and concentratedunder reduced pressure. The compound was purified via columnchromatography (hexane-ethyl acetate). Reaction temperatures, times, andconversion for enyne Cope rearrangement/alkylidene reduction based onthe enyne used in the reaction are given below in Table 8. Using theforegoing method, compounds 7 ad, 7 dd, 7 ld, and 7 md were prepared,and are described in further detail herein below.

TABLE 8 Temp Time Enyne (° C.) (hrs.) 3a 140  4 3b 130 16 3l 130 16 3m130 16

-   -   a.        5-(2-(2λ5-PROPA-1,2-DIEN-1-YL)CYCLOHEXYL)-5,5-DICYANOPENT-2-YN-1-YL        ACETATE (7AD).

Pale yellow oil, 48% yield, 76 mg, 2:1 dr. Purified using 10% EtOAc inhexane. ¹H NMR (500 MHz, CDCl₃) δ 5.44-5.11 (m, 1H), 4.94-4.76 (m, 2H),4.76-4.71 (m, 2H), 3.25-2.81 (m, 2H), 2.33-2.17 (m, 1H), 2.12 (s, 4H),2.05-1.81 (m, 3H), 1.81-1.45 (m, 2H), 1.43-1.22 (m, 4H). ¹³C NMR (125MHz, CDCl₃) δ 209.4, 208.8, 170.1, 115.0, 114.3, 93.0, 86.7, 80.9, 80.8,77.9, 77.6, 76.0, 75.5, 52.0, 52.0, 46.2, 45.2, 42.5, 41.1, 36.5, 34.6,32.7, 28.3, 27.8, 26.8, 25.8, 25.5, 25.0, 23.9, 20.7, 20.0. HRMS:(ESI-TOF) m/z: [M+Na]⁺ Calcd for C₁₈H₂₀N₂O₂Na 319.1417; Found 319.1422.

-   -   b. ETHYL        4-(5-ACETOXY-1,1-DICYANOPENT-3-YN-1-YL)-3-(2λ5-PROPA-1,2-DIEN-1-YL)CYCLOHEXANE-1-CARBOXYLATE        (7DD).

Pale yellow oil, 49% yield, 70 mg, ˜2:1:1 dr. Purified using 15% EtOAcin hexane. ¹H NMR (500 MHz, CDCl₃) δ 5.41-5.08 (m, 1H), 4.96-4.78 (m,2H), 4.70 (m, 2H), 4.26-4.08 (m, 2H), 3.28-2.89 (m, 2H), 2.78-1.87 (m,9H), 1.77 (dtd, J=19.9, 13.1, 4.0 Hz, 1H), 1.68-1.44 (m, 2H), 1.42-1.16(m, 5H). ¹³C NMR (125 MHz, cdcl3) δ 209.6, 208.9, 208.8, 174.7, 174.2,173.8, 170.1, 114.8, 114.7, 114.5, 114.1, 114.0, 113.6, 92.5, 92.1,86.1, 81.2, 81.1, 81.0, 77.8, 77.6, 77.3, 76.6, 76.5, 76.1, 60.7, 60.6,52.0, 51.9, 45.5, 45.4, 44.3, 41.9, 41.6, 40.8, 40.6, 40.3, 38.1, 38.0,37.1, 36.5, 36.0, 35.0, 34.6, 28.2, 28.0, 27.7, 27.6, 27.5, 27.0, 26.1,24.5, 22.9, 20.7, 14.2. Relative stereochemistry and dr was determinedusing COSY, gHSQC, gHMBC, gHSQCTOCSY, and TOCSY. HRMS: (ESI-TOF) m/z:[M+Na]⁺ Calcd for C₁₂H₂₄N₂O₄Na 391.1628; Found 391.1637.

-   -   c.        5-(4-ACETAMIDO-2-(2λ5-PROPA-1,2-DIEN-1-YL)CYCLOHEXYL)-5,5-DICYANOPENT-2-YN-1-YL        ACETATE (7LD).

Pale yellow oil, 68% yield, >20:1 dr. Purified using 100% EtOAc. ¹H NMR(500 MHz, CDCl₃) δ 5.90 (d, J=7.1 Hz, 1H), 5.12 (dt, J=9.2, 6.6 Hz, 1H),4.88 (dddd, J=33.2, 11.3, 6.6, 1.2 Hz, 2H), 4.71 (t, J=2.1 Hz, 2H), 4.20(dp, J=8.0, 3.9 Hz, 1H), 3.21 (dt, J=17.0, 2.1 Hz, 1H), 3.09 (dt,J=16.9, 2.1 Hz, 1H), 2.58-2.39 (m, 1H), 2.16-1.81 (m, 10H), 1.73-1.46(m, 2H). ¹³C NMR (125 MHz, CDCl₃) δ 208.8, 170.3, 169.9, 114.9, 114.3,92.4, 81.4, 77.6, 77.4, 77.1, 77.0, 76.9, 52.1, 45.3, 43.7, 40.6, 37.3,37.0, 28.9, 28.2, 23.6, 23.1, 20.8. Relative stereochemistry determinedusing HSQC, HMBC, and TOCSY (2.46, 5.12, and 5.90 ppm). HRMS: (ESI-TOF)m/z: [M+Na]⁺ Calcd for C₂₀H₂₃N₃O₃Na 376.1647; Found 376.1647.

-   -   d.        5-(7-(2λ5-PROPA-1,2-DIEN-1-YL)-1,4-DIOXASPIRO[4.5]DECAN-8-YL)-5,5-DICYANOPENT-2-YN-1-YL        ACETATE (7MD).

Pale yellow oil, 57% yield, 83 mg, 1.5:1 dr. Purified using 20% EtOAc inhexane. ¹H NMR (500 MHz, CDCl₃) δ 5.78-5.12 (m, 1H), 4.99-4.68 (m, 4H),4.13-3.90 (m, 4H), 3.32-2.87 (m, 2H), 2.73-2.20 (m, 1H), 2.17-1.81 (m,7H), 1.74-1.57 (m, 2H), 1.27 (s, 1H). ¹³C NMR (125 MHz, CDCl₃) δ 209.0,209.0, 170.1, 114.8, 114.7, 114.0, 113.7, 107.3, 106.8, 91.9, 87.9,81.1, 81.0, 77.7, 77.5, 76.6, 75.1, 64.6, 64.6, 64.5, 64.1, 52.0, 52.0,45.3, 44.2, 42.2, 40.4, 40.2, 39.9, 39.7, 37.3, 34.4, 34.0, 27.9, 26.9,25.8, 21.9, 20.7. HRMS: (ESI-TOF) m/z: [M+Na]⁺ Calcd for C₂₀H₂₂N₂O₄Na377.1472; Found 377.1483.

8. General Procedure for One-Pot Cope Rearrangement/Tsuji-TrostAllylation.

Enyne 3 e was dissolved in toluene (0.1 M with respect to the enyne) andN₂ was bubbled through the solution for five minutes. The solution wasthen heated to 150° C. for 1 hour using microwave irradiation. When thereaction was done, the solution was cooled to room temperature and thesolvent was removed under reduced pressure. The crude product from theCope rearrangement was then re-dissolved in THF (0.5 M with respect toallene 4 e) and added to a suspension of NaH (1.1 equivalent) in THF at0° C. The allyl acetate electrophile (2 eq) and Pd(PPh₃)₄ (5 mol%) werethen added to the solution and the reaction was warmed to roomtemperature. Upon completion of the reaction (monitored by TLC, 30 min-2hours), a saturated solution of NH₄Cl was added to quench the NaH andthe crude material was extracted with ethyl acetate. The organic layerwas then washed with H₂O and brine, dried with Na₂SO₄, and concentratedunder reduced pressure. The compound was then purified via columnchromatography (hexane-ethyl acetate).

-   -   a. TERT-BUTYL        (Z)-3-(2-(λ2-AZANYLIDENE)-1-CYANO-2λ3-ETHYLIDENE)-2-(1-PHENYLALLYL)-4-(2λ5-PROPA-1,2-DIEN-1-YL)-8-AZABICYCLO[3.2.1]OCTANE-8-CARBOXYLATE        (8C).

Colorless oil, 61% yield, 83 mg, d.r>20:1. Purified using 10% EtOAc inhexane. ¹H NMR (500 MHz, DMSO-d₆) δ 7.42-7.37 (m, 2H), 7.35-7.32 (m,2H), 7.31-7.27 (m, 1H), 5.91 (ddd, J=17.0, 10.2, 9.0 Hz, 1H), 5.39 (q,J=6.9 Hz, 1H), 5.11-5.03 (m, 2H), 5.01-4.89 (m, 2H), 4.49 (d, J=7.0 Hz,1H), 4.08 (d, J=7.1 Hz, 1H), 3.74-3.65 (m, 2H), 3.27 (d, J=11.2 Hz, 1H),1.86-1.68 (m, 2H), 1.62-1.45 (m, 2H), 1.37 (s, 9H). ¹³C NMR (125 MHz,DMSO-d₆) δ 209.1, 180.2, 154.5, 141.5, 138.7, 129.3, 128.5, 127.4,117.7, 112.7, 111.9, 90.5, 88.6, 80.2, 78.6, 58.6, 55.7, 55.5, 53.7,49.0, 28.6, 28.4, 28.1. HRMS: (ESI-TOF) m/z: [M+Na]⁺ for C₂₇H₂₉N₃O₂Na450.1252; Found 450.2171. R_(f)=0.6 (30% EtOAc in hexane). Note:Relative stereochemistry generated during the allylation is inferred bycomparison to the product of the Cope rearrangement of 8 a (reactiondetails shown below). This was done based on results previouslypublished by our group⁷ regarding the diasteroselective Coperearrangement and NOE confirming the stereochemistry of the ring.

Procedure: Enyne 8 a (30 mg, 70.17 μmol) was dissolved in toluene (0.1M) and N₂ was bubbled through the solution for five minutes. Thesolution was then heated to 150° C. for 8 hours using microwaveirradiation. When the reaction was done, the solution was cooled to roomtemperature and the solvent was removed under reduced pressure. Thecrude product was purified via column chromatography (10% EtOAc inhexane) to afford 8 c in 71% yield (21.3 mg).

-   -   b. TERT-BUTYL        3-((3E,5E)-1,1-DICYANOHEPTA-3,5-DIEN-1-YL)-4-(2λ5-PROPA-1,2-DIEN-1-YL)-8-AZABICYCLO[3.2.1]OCT-2-ENE-8-CARBOXYLATE        (8D).

Yellow oil, 41% yield, 52 mg. Purified using 10% EtOAc in hexane. ¹H NMR(500 MHz, DMSO-d₆) δ 6.49 (d, J=5.4 Hz, 1H), 6.33 (dd, J=15.1, 10.3 Hz,1H), 6.19-6.09 (m, 1H), 5.80 (dq, J=13.8, 6.7 Hz, 1H), 5.51 (dt, J=14.9,7.2 Hz, 1H), 5.26 (dt, J=8.1, 6.6 Hz, 1H), 4.89 (ddd, J=11.0, 6.7, 1.6Hz, 1H), 4.81 (ddd, J=11.1, 6.6, 1.4 Hz, 1H), 4.55 (t, J=5.4 Hz, 1H),4.35 (d, J=7.7 Hz, 1H), 3.00 (dd, J=7.4, 3.4 Hz, 2H), 2.89 (d, J=8.0 Hz,1H), 2.06 (dddd, J=13.2, 10.5, 7.9, 2.3 Hz, 1H), 1.86-1.78 (m, 1H),1.78-1.69 (m, 4H), 1.62-1.51 (m, 1H), 1.47-1.36 (m, 9H). ¹³C NMR (125MHz, DMSO-d₆) δ 208.4, 151.9, 136.9, 133.8, 130.5, 130.1, 127.5, 120.3,114.5, 114.1, 90.5, 78.5, 76.5, 56.6, 54.3, 45.7, 40.9, 40.6, 40.0,39.9, 39.8, 39.7, 39.6, 39.5, 39.4, 39.4, 39.2, 39.0, 32.6, 27.7, 27.1,17.2. HRMS: (ESI-TOF) m/z: [M+Na]⁺ Calcd for C₂₄H₂₉N₅O₂Na 414.2152;Found 414.2155. R_(f)=0.4 (20% EtOAc in hexane). Relativestereochemistry was determined by analysis of 8.

9. General Procedure for Pauson-Khand Reaction.

Procedure 1: A flame-dried Schlenk flask was charged with 5 mol%[Rh(CO)₂Cl]₂ and the flask was evacuated and refilled with CO gas. Theallenyne 5 and toluene (0.01 M with respect to 5) were then added to theflask and a full balloon of CO gas was bubbled through the solution. Theballoon was then replaced with a second full balloon of CO gas and thereaction was heated to 90° C. When the reaction was complete (monitoredby TLC, 6-18 hrs) the solution was cooled to room temperature andsolvent was removed under reduced pressure. The product was purifiedusing column chromatography (hexane-ethyl acetate).

Procedure 2: A flame-dried Schlenk flask was charged with a solution ofallenyne 5 in p-xylenes (0.005 M) under nitrogen. A full balloon of COwas then bubbled through the solution before being replaced with asecond balloon of CO. The [Rh(CO)₂Cl]₂ catalyst (10 mol%) was then addedto the reaction under an atmosphere of CO gas. The reaction was thenheated to 110° C. using a preheated oil bath. Upon completion of thereaction (monitored by TLC, 6-18 hrs) the solution was cooled to roomtemperature and solvent was removed under reduced pressure. The productwas purified using column chromatography (hexane-ethyl acetate).

Using the foregoing methods, compounds 6 aa, 6 cd, 6 dd, 6 de, 6 ed, 6hd, 6 jd, 6 kd, and 6 md were prepared, and are described in furtherdetail herein below.

a. 2-OXO-2,4A,5,6,7,10-HEXAHYDROBENZO[F]AZULENE-9,9(3H) -DICARBONITRILE(6AA).

Orange oil, 52% yield via procedure 2, 47 mg (30% yield via procedure1). Purified using 40% EtOAc in hexane. ¹H NMR (500 MHz, CDCl₃) δ 6.40(t, J=3.9 Hz, 1H), 6.26 (s, 1H), 5.74 (s, 1H), 3.67 (d, J=15.5 Hz, 1H),3.46 (s, 1H), 3.35 (d, J=15.5 Hz, 1H), 3.05 (dd, J=30.2, 21.1 Hz, 2H),2.19 (m, 2H), 1.88 (dt, J=8.1, 3.8 Hz, 2H), 1.73 (dp, J=13.9, 4.7 Hz,1H), 1.58 (tt, J=13.5, 7.5 Hz, 1H). ¹³C NMR (125 MHz, CDCl₃) δ 203.4,162.0, 136.3, 136.2, 132.7, 132.2, 131.2, 114.7, 114.4, 41.9, 39.9,39.5, 35.4, 29.7, 25.3, 18.0. HRMS: (ESI-TOF) m/z: [M+H]⁺ Calcd forC₁₆H₁₅N₂O 251.1179; Found 251.1173; [M +Na]⁺ Calcd for C₁₆H₁₄N₂ONa273.0998; Found 273.1010. R_(f)=0.53 (50% EtOAc in hexane)

-   -   b.        (9,9-DICYANO-6-METHYL-2-OXO-2,3,3A,4,4A,5,6,7,9,10-DECAHYDROBENZO[F]AZULEN-1-YL)METHYL        ACETATE (6CD).

Yellow oil, 32% yield, 35 mg, d.r >20:1 (via procedure 1). Purifiedusing 20% EtOAc in hexane. ¹H NMR (500 MHz, CDCl₃) δ 6.35 (dd, J=5.0,2.3 Hz, 1H), 5.84 (d, J=3.3 Hz, 1H), 4.88 (d, J=12.9 Hz, 1H), 4.80 (d,J=13.0 Hz, 1H), 3.69 (d, J=15.5 Hz, 1H), 3.61 (d, J=15.5 Hz, 1H), 3.53(s, 1H), 3.14-2.99 (m, 2H), 2.28 (dt, J=17.9, 4.6 Hz, 1H), 2.07 (s, 3H),1.89 (dt, J=14.3, 2.5 Hz, 1H), 1.81 (dt, J=10.4, 2.4 Hz, 1H), 1.78-1.68(m, 2H), 1.58 (td, J=12.5, 5.1 Hz, 1H), 1.03 (d, J=6.0 Hz, 3H). ¹³C NMR(125 MHz, CDCl₃) δ 201.83, 170.72, 159.66, 141.10, 135.96, 134.64,132.14, 130.96, 114.77, 114.67, 54.42, 40.61, 38.97, 37.74, 36.94,35.45, 33.74, 23.87, 21.35, 20.86. HRMS: (ESI-TOF) m/z: [M+H]⁺ Calcd forC₂₀H₂₁N₂O₃ 337.1547; Found 337.1541. HSQC, HMBC, and NOESY used todetermine relative stereochemistry.

-   -   c. ETHYL        1-(ACETOXYMETHYL)-9,9-DICYANO-2-OXO-2,3,4A,5,6,7,9,10-OCTAHYDROBENZO[F]AZULENE-6-CARBOXYLATE        (6DD).

Orange solid, 41-44% yield (26-220 mg) (via procedure 1). Purified using40% EtOAc in hexane. ¹H NMR (500 MHz, CDCl₃) δ 6.39 (t, J=3.8 Hz, 1H),5.84 (d, J=3.2 Hz, 1H), 4.88 (d, J=13.0 Hz, 1H), 4.81 (d, J=13.0 Hz,1H), 4.18 (q, J=7.2 Hz, 2H), 3.70 (d, J=15.5 Hz, 1H), 3.64 (d, J=15.6Hz, 2H), 3.12 (d, J=21.1 Hz, 1H), 3.05 (d, J=21.6 Hz, 1H), 2.64-2.55 (m,1H), 2.50 (dt, J=19.0, 5.4 Hz, 1H), 2.47-2.39 (m, 1H), 2.26 (dt, J=13.7,2.8 Hz, 1H), 2.07 (s, 3H), 1.98 (td, J=13.0, 5.2 Hz, 1H), 1.28 (t, J=7.1Hz, 3H). ¹³C NMR (125 MHz, CDCl₃) δ 201.6, 174.0, 170.8, 159.1, 141.8,136.9, 132.8, 131.3, 130.6, 114.6, 114.4, 61.2, 54.5, 40.8, 39.1, 37.2,35.1, 34.9, 32.1, 27.8, 21.0, 14.3. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd forC₂₂H₂₃N₂O₅ 395.1601; Found 395.1593; [M+Na]⁺ Calcd for C₂₂H₂₂N₂O₅Na417.1421; Found 417.1418. R_(f)=0.42 (50% EtOAc in hexane). Relativestereochemistry is assumed to be consistent with 6 cd.

-   -   d. ETHYL 9,9-DICYANO-2-OXO-1        -(TRIMETHYLSILYL)-2,3,4A,5,6,7,9,10-OCTAHYDROBENZO[F]AZULENE-6-CARBOXYLATE        (6DE).

Orange oil, 48% yield, 52 mg (via procedure 1). Purified using 20% EtOAcin hexane. ¹H NMR (500 MHz, CDCl₃) δ 6.37 (s, 1H), 5.74 (s, 1H), 4.20(qd, J=7.0, 6.4, 1.2 Hz, 2H), 3.74-3.48 (m, 3H), 3.03 (dd, J=23.3, 20.5Hz, 2H), 2.72-2.57 (m, 1H), 2.57-2.34 (m, 2H), 2.32-2.22 (m, 1H), 1.96(m, 1H), 1.30 (t, J=7.0 3H), 0.33 (s, 9H). ¹³C NMR (125 MHz, CDCl₃) δ207.9, 174.2, 166.5, 150.0, 140.5, 131.7, 130.3, 130.0, 114.9, 114.6,77.4, 77.2, 76.9, 61.1, 42.1, 39.1, 37.6, 34.8, 33.9, 32.1, 27.7, 14.3,−0.2. HRMS: (ESI-TOF) m/z: [M+Na]⁺ Calcd for C₂₂H₂₆N₂O₃SiNa 417.1605;Found 417.1613. R_(f)=0.58 (40% EtOAc in hexane). Relativestereochemistry is assumed to be consistent with 6 cd.

-   -   e. TERT-BUTYL 1-(ACETOXYM        ETHYL)-10,10-DICYANO-2-OXO-3,4A,5,6,7,8,10,11-OCTAHYDRO-2H-5,8-EPIMINOCYCLO        PENTA[B]HEPTALENE-12-CARBOXYLATE (6ED).

Orange solid, 75% yield, 68 mg (via procedure 1). Purified using 35%EtOAc in hexane. ¹H NMR (500 MHz, DMSO-d₆) δ 6.63 (d, J=5.5 Hz, 1H),6.13 (d, J=3.3 Hz, 1H), 4.80 (s, 2H), 4.58 (d, J=8.0 Hz, 1H), 4.54 (t,J=5.7 Hz, 1H), 4.01 (d, J=15.7 Hz, 1H), 3.78 (d, J=15.7 Hz, 1H), 3.63(s, 1H), 3.17 (d, J=21.2 Hz, 1H), 2.97 (d, J=21.3 Hz, 1H), 2.202.10 (m,1H), 2.00 (s, 3H), 1.88 (dd, J=11.8, 9.2 Hz, 1H), 1.78 (tt, J=11.7, 6.4Hz, 1H), 1.73-1.64 (m, 1H), 1.41 (s, 9H). ¹³C NMR (125 MHz, DMSO-d₆) δ200.8, 169.5, 159.8, 140.0, 134.5, 133.6, 130.7, 130.0, 114.5, 114.5,79.0, 59.2, 56.2, 53.6, 44.9, 39.8, 37.5, 34.4, 32.2, 27.6, 27.1, 20.0.HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₅H₂₈N₃O₅ 450.2023; Found450.2012; [M+Na]⁺ Calcd for C₂₅H₂₇N₃O₅Na 472.1843; Found 472.1837.R_(f)=0.2 (40% EtOAc in hexane). Relative stereochemistry was determinedbased on analysis of 8.

-   -   f. TERT-BUTYL        1-(ACETOXYMETHYL)-10,10-DICYANO-4-METHYL-2-OXO-3,4A,5,6,7,8,10,11-OCTAHYDRO-2H-5,8-EPIMINO        CYCLOPENTA[B]HEPTALENE-12 -CARBOXYLATE (6HD).

Brown oil, 29% yield, 15.4 mg (via procedure 1). Purified using 40%EtOAc in hexane. ¹H NMR (500 MHz, DMSO-d₆) δ 6.67 (dd, J=5.7, 1.3 Hz,1H), 4.81 (d, J=8.6 Hz, 1H), 4.77 (s, 2H), 4.56 (t, J=5.4 Hz, 1H), 4.04(d, J=16.5 Hz, 1H), 3.69 (d, J=16.5 Hz, 1H), 3.57 (s, 1H), 3.17 (d,J=21.1 Hz, 1H), 2.94 (d, J=21.1 Hz, 1H), 2.16-2.06 (m, 4H), 2.00 (s,3H), 1.91-1.86 (m, 1H), 1.77-1.66 (m, 2H), 1.38 (s, 9H). ¹³C NMR (125MHz, DMSO-d₆) δ 199.9, 169.5, 160.6, 153.0, 138.7, 138.1, 133.9, 130.9,129.4, 114.6, 114.5, 79.2, 59.2, 53.9, 53.8, 53.0, 49.3, 40.7, 37.7,36.5, 32.3, 27.5, 20.0, 19.5. HRMS (ESI-TOF) m/z: [M+Na]⁺ Calcd forC₂₆H₂₉N₃O₅Na 486.1999; Found 486.2012. R_(f)=0.43 (50% EtOAc in hexane).Relative stereochemistry was determined based on analysis of 8.

-   -   g.        (12-(TERT-BUTOXYCARBONYL)-10,10-DICYANO-2-OXO-3,4A,5,6,7,8,10,11        -OCTAHYDRO-2H-5,8-EPIMINOCYCLOPENTA[B]HEPTALENE-1,4-DIYL)BIS(METHYLENE)        DIACETATE (6JD).

Orange solid, 59% yield via procedure 2, 56 mg (44% yield via procedure1). Purified using 40% EtOAc in hexane. Note: Use of toluene-d₈ wasrequired to obtain NMR spectra at 80° C., as DMSO-d₆ resulting in rapiddecomposition of the compound. ¹H NMR (500 MHz, Toluene-d₈) δ 6.19 (d,J=5.5 Hz, 1H), 5.09 (d, J=13.1 Hz, 1H), 4.87 (d, J=7.8 Hz, 1H), 4.69 (d,J=14.0 Hz, 2H), 4.54 (d, J=13.0 Hz, 1H), 4.25 (s, 1H), 3.30-2.96 (m,4H), 2.62 (d, J=4.6 Hz, 1H), 1.94-1.66 (m, 7H), 1.53-1.43 (m, 2H), 1.30(d, J=4.7 Hz, 9H), 1.21 (dt, J=15.3, 8.0 Hz, 1H). ¹³C NMR (125 MHz,Toluene-ci_(s)) δ 198.3, 169.9, 169.6, 157.6, 154.1, 142.5, 137.7,137.4, 135.2, 134.6, 130.4, 129.4, 129.2, 129.0, 128.8, 128.6, 128.3,128.1, 127.9, 125.7, 125.4, 125.2, 125.0, 115.0, 114.4, 80.5, 63.9,54.9, 54.8, 54.4, 49.7, 41.0, 39.5, 39.1, 33.4, 28.9, 28.4, 21.4, 20.9,20.7, 20.6, 20.4, 20.3, 20.2, 20.2, 20.1, 20.0. HRMS (ESI-TOF) m/z:[M+Na]⁺ Calcd for C₂₈H₃₁N₃O₇Na 544.2054; Found 544.2068. R_(f)=0.42 (50%EtOAc in hexane). Relative stereochemistry was determined based onanalysis of 8.

-   -   h.        (10,10-DICYANO-2-OXO-3,4A,5,8,10,11-HEXAHYDRO-2H-5,8-METHANOCYCLOPENTA[B]HEPTALENE-1,4-DIYL)BIS        (METHYLENE) DIACETATE (6KD).

Orange solid, 50% yield, 200 mg (via procedure 2). Purified using 30%EtOAc in hexane. ¹H NMR (500 MHz, CDCl₃) δ 6.89 (d, J=6.9 Hz, 1H), 6.41(dd, J=5.5, 2.8 Hz, 1H), 5.91 (dd, J=5.5, 3.1 Hz, 1H), 4.89-4.76 (m,4H), 3.69 (d, J=17.0 Hz, 1H), 3.49 (d, J=17.0 Hz, 1H), 3.42-3.31 (m,2H), 3.19-3.07 (m, 2H), 2.98 (dt, J=6.7, 3.5 Hz, 1H), 2.07 (d, J=9.8 Hz,6H), 1.91 (dt, J=9.9, 4.7 Hz, 1H), 1.57 (d, J=10.2 Hz, 1H). ¹³C NMR (125MHz, CDCl₃) δ 199.8, 170.7, 170.5, 159.5, 142.0, 141.7, 139.0, 138.0,134.5, 131.1, 126.9, 114.6, 113.8, 63.6, 54.7, 42.9, 41.6, 41.1, 40.0,38.9, 38.9, 37.1, 20.8, 20.8. HRMS (ESI-TOF) m/z: [2M+Na]⁺ Calcd forC₄₈H₄₄N₄O₁₀Na 859.2950; Found 859.2971. R_(f)=0.37 (40% EtOAc inhexane). Relative stereochemistry was determined based on analysis of9c.

-   -   i. (9,9-DICYANO-2-OXO-2,4A,5,7,8,8A,9,10-OCTAHYDRO-3H        -SPIRO[BENZO[F]AZULENE-6,2′-[1,3]DIOXOLAN]-1-YL)METHYL ACETATE        (6MD).

Pale yellow oil, 50% yield, 25 mg (via procedure 2). Purified using 40%EtOAc in hexane. ¹H NMR (500 MHz, CDCl₃) δ 5.94-5.65 (m, 1H), 4.94-4.78(m, 2H), 4.09-3.91 (m, 5H), 3.79-3.31 (m, 2H), 3.25-3.06 (m, 2H),2.98-2.55 (m, 1H), 2.48-1.85 (m, 9H), 1.76-1.60 (m, 2H). ¹³C NMR (125MHz, CDCl₃) δ 201.8, 201.4, 170.8, 170.7, 160.1, 158.7, 141.2, 140.8,133.4, 133.3, 132.7, 132.3, 115.1, 115.0, 114.7, 112.7, 107.0, 106.9,65.0, 64.9, 64.7, 64.5, 54.7, 54.6, 47.6, 45.8, 42.1, 42.0, 42.0, 40.8,40.3, 39.3, 39.2, 38.0, 37.9, 34.5, 34.2, 34.0, 29.8, 22.6, 20.9, 20.8.HRMS (ESI-TOF) m/z: [M+Na]⁺ Calcd for C₂₁H₂₂N₂O₅Na 405.1437; Found405.1437.

10. Procedure for Diels Alder Cycloaddition of 8 e: Preparation of12-(Tert -Butyl) 2-Methyl6,6-Dicyano-1-Methylene-5,6,8,9,10,11,11A,11B-Octahydro-8,11-Epimino-2,4a-Epdxycyclohepta[A]Naphthalene-2,12(1h)-Dicarboxylate(9).

8 e (70 mg, 0.155 mmol) was dissolved in 1.6 mL toluene and sealed in amicrowave tube. The solution was then heated to 150° C. for 9 hoursusing a microwave reactor. The solvent was then evaporated and the crudeproduct was purified via column chromatography (25% EtOAc in hexane).

White solid, 39% yield, 27 mg. ¹H NMR (500 MHz, DMSO-d₆) δ 6.62 (d,J=5.4 Hz, 2H), 6.59 (d, J=5.6 Hz, 1H), 6.28 (d, J=5.4 Hz, 1H), 5.45 (s,1H), 5.26 (d, J=1.6 Hz, 1H), 4.68-4.61 (m, 2H), 3.85 (s, 3H), 3.24 (d,J=15.0 Hz, 1H), 2.97 (d, J=15.0 Hz, 1H), 2.32 (d, J=10.9 Hz, 1H),2.23-2.13 (m, 2H), 1.97 (ddd, J=11.5, 8.8, 2.1 Hz, 1H), 1.80 (ddt,J=12.8, 11.5, 6.6 Hz, 1H), 1.50 (dt, J=13.3, 7.8 Hz, 1H), 1.41 (s, 9H).¹³C NMR (125 MHz, DMSO-d₆) δ 167.2, 153.2, 148.4, 137.8, 136.7, 131.3,127.4, 114.8, 114.4, 107.3, 90.6, 86.2, 80.1, 53.2, 52.8, 47.2, 45.9,37.5, 37.4, 33.7, 30.9, 29.2, 28.6.

It will be apparent to those skilled in the art that variousmodifications and variations can be made in the present disclosurewithout departing from the scope or spirit of the disclosure. Otherembodiments of the disclosure will be apparent to those skilled in theart from consideration of the specification and practice of thedisclosure disclosed herein. It is intended that the specification andexamples be considered as exemplary only, with a true scope and spiritof the disclosure being indicated by the following claims.

What is claimed is:
 1. A method of synthesizing a terpenoid scaffold,the method comprising: reacting an allenyne precursor in the presence ofCO gas and [Rh(CO)₂Cl]₂; wherein the allenyne precursor has a formularepresented by a structure:

wherein E is —CN or —(C═O)OR¹⁰; wherein R¹⁰ is C1-C6 alkyl; wherein eachof R^(1a), R^(1b), R^(1c), and R^(1d) is independently hydrogen, C1-C6alkyl, aryl, or —(CH₂),(C═O)OR¹¹; or wherein R^(1a) and R^(1c) arecovalently bonded and, together with more intermediate carbons, comprise—CH₂CH₂—, or —CH═CH—; wherein m is an integer selected from 0, 1, 2, and3; and wherein R¹¹ is C1-C6 alkyl; wherein R² is hydrogen, C1-C6 alkyl,aryl, or —(CH₂)_(n)(C═O)OR¹²; wherein n is an integer selected from 0,1, 2, and 3; and wherein R¹² is C1-C6 alkyl; wherein A^(l) is—C(R²⁰)(R²¹)—, —NR²²—or —CH₂—; wherein R²⁰ is hydrogen, C1-C6 alkyl, or—(CH₂)_(p)(C═O)OR³⁰; wherein R³° is C1-C6 alkyl; and wherein p is aninteger selected from 0, 1, 2, and 3; wherein R²¹ is hydrogen, C1-C6alkyl, or —(CH₂)_(q)(C═O)OR³⁰; wherein R³¹ is C1-C6 alkyl; and wherein qis an integer selected from 0, 1, 2, and 3; and wherein R²² is C1-C6alkyl, or —(C═O)OR³²; and wherein R³² is C1-C6 alkyl; and wherein R³ ishydrogen, C1-C6 alkyl, aryl, trimethylsilyl, or —(CH₂),(C═O)OR¹⁵;wherein r is an integer selected from 0, 1, 2, and 3; and wherein R¹⁵ isC1-C6 alkyl; thereby synthesizing the terpenoid scaffold; wherein theterpenoid scaffold has a formula represented by a structure:


2. The method of claim 1, wherein E is —CN or —(C═O)OCH₃.
 3. The methodof claim 1, wherein E is —CN.
 4. The method of claim 1, wherein each ofR^(1a), R^(1b), R^(1c), and R^(1d) is independently hydrogen, methyl,phenyl, or —CH₂(C═O)OCH₃.
 5. The method of claim 1, wherein each ofR^(1b) and R^(1d) are hydrogen; and wherein R^(1a) and R^(1c)arecovalently bonded and, together with more intermediate carbons, comprise—CH₂CH₂—or —CH═CH—.
 6. The method of claim 1, wherein R² is hydrogen,methyl, phenyl, or —CH₂(C═O)OCH₃.
 7. The method of claim 1, wherein A¹is —CH₂—, —CHCH₃, —CH(C═O)OCH₂CH₃, or —N(C═O)OC(CH₃)₃.
 8. The method ofclaim 1, wherein R³ is hydrogen, methyl, phenyl, trimethylsilyl, or—CH₂(C═O)OCH₃.
 9. A compound, wherein the compound has a formularepresented by a structure:

wherein E is —CN or —(C═O)OR¹⁰; wherein R¹⁰ is C1-C6 alkyl; wherein A¹is —C(R²⁰)(R²¹)—, —NR²²— or —CH₂—; wherein R²⁰ is hydrogen, C1-C6 alkyl,or —(CH₂)_(p)(C═O)OR³⁰; wherein R³⁰ is C1-C6 alkyl; and wherein p is aninteger selected from 0, 1, 2, and 3; wherein R²¹ is hydrogen, C1-C6alkyl, or —(CH₂)_(p)(C═O)OR³¹; wherein R³¹ is C1-C6 alkyl; and wherein qis an integer selected from 0, 1, 2, and 3; and wherein R²² is C1-C6alkyl, or —(C═O)OR³²; and wherein R³² is C1-C6 alkyl; wherein each ofR^(1a), R^(1b) , R^(1c), and R^(1d) is independently hydrogen, C1-C6alkyl, aryl, or —(CH₂)_(m)(C═O)OR¹¹; or wherein R^(i)a and R^(1c)arecovalently bonded and, together with more intermediate carbons, comprise—CH₂CH₂—, or —CH═CH—; wherein m is an integer selected from 0, 1, 2, and3; and wherein R¹¹ is C1-C6 alkyl; wherein R² is hydrogen, C1-C6 alkyl,aryl, or —(CH₂)n(C═O)OR¹²; wherein n is an integer selected from 0, 1,2, and 3; and wherein R¹² is C1-C6 alkyl; wherein R³ is hydrogen, C1-C6alkyl, aryl, trimethylsilyl, or —(CH₂),(C═O)OR¹⁵; wherein r is aninteger selected from 0, 1, 2, and 3; and wherein R¹⁵ is C1-C6 alkyl.10. The compound of claim 9, wherein E is —CN or —(C═O)OCH₃.
 11. Thecompound of claim 9, wherein E is —CN.
 12. The compound of claim 9,wherein each of R^(1a), R^(1b), R^(1c), and R^(1d) is independentlyhydrogen, methyl, phenyl, or —CH₂(C═O)OCH₃.
 13. The compound of claim 9,wherein each of R^(1b) and R^(1d) are hydrogen; and wherein R^(1a) andR^(1c) are covalently bonded and, together with more intermediatecarbons, comprise —CH₂CH₂—or —CH═CH—.
 14. The compound of claim 9,wherein R² is hydrogen, methyl, phenyl, or —CH₂(C═O)OCH₃.
 15. Thecompound of claim 9, wherein Ai is —CH₂—, —CHCH₃, —CH(C═O)OCH₂CH₃, or—N(C═O)OC(CH₃)3.
 16. The compound of claim 9, wherein R³ is hydrogen,methyl, phenyl, trimethylsilyl, or —CH₂(C═O)OCH₃.
 17. The compound ofclaim 9, wherein R²⁰ is hydrogen; and wherein R²¹ is hydrogen, C1-C6alkyl, or —(C═O)OCH₂CH₃.
 18. The compound of claim 9, wherein R²² isC1-C6 alkyl or —(C═O)OCH₂CH₃.
 19. The compound of claim 9, wherein thecompound has a formula represented by a structure:


20. The compound of claim 9, wherein the compound has a formularepresented by a structure: